5-phenylthiazole derivatives and use as Pi3 kinase inhibitors

ABSTRACT

Compounds of formula I 
                         
in free or salt form, wherein R 1 , R 2 , R 3 , R 4  and R 5  have the meanings as indicated in the specification, are useful for treating diseases mediated by phosphatidylinositol 3-kinase. Pharmaceutical compositions that contain the compounds and processes for preparing the compounds are also described.

The present invention relates to organic compounds, their preparationand their use as pharmaceuticals.

In a first aspect, the present invention provides compounds of formula I

in free or salt form, whereinR¹ is hydrogen or aminocarbonyl optionally substituted by nitrile, or R¹is C₁-C₈-alkylcarbonyl or C₁-C₈-alkylaminocarbonyl either of which beingoptionally substituted by halogen, hydroxy, amino, C₁-C₈-alkylamino,di(C₁-C₈-alkyl)amino, carboxy, C₁-C₈-alkoxycarbonyl, nitrile, phenyl,C₁-C₈-haloalkyl, or by C₁-C₈-alkyl optionally substituted by hydroxy,or R¹ is C₁-C₈-alkylcarbonyl or C₁-C₈-alkylaminocarbonyl either of whichbeing optionally substituted by C₃-C₈-cycloalkyl optionally substitutedby hydroxy,or R¹ is C₁-C₈-alkylcarbonyl or C₁-C₈-alkylaminocarbonyl either of whichbeing optionally substituted by C₁-C₈-alkoxy optionally substituted byhydroxy,or R¹ is C₁-C₈-alkylcarbonyl or C₁-C₈-alkylaminocarbonyl either of whichbeing optionally substituted by phenyl optionally substituted by hydroxyor C₁-C₈-alkyl,or R¹ is C₁-C₈-alkylcarbonyl or C₁-C₈-alkylaminocarbonyl either of whichbeing optionally substituted by a 5- or 6-membered heterocyclic ringhaving one or more ring hetero atoms selected from the group consistingof oxygen, nitrogen and sulphur, that ring being optionally substitutedby hydroxy, C₁-C₈-alkyl or C₁-C₈-alkoxy,or R¹ is —(C═O)—(NH)_(a)-Het where a is 0 or 1 and Het denotes a 4-, 5-or 6-membered heterocyclic ring having one or more ring hetero atomsselected from the group consisting of oxygen, nitrogen and sulphur, thatring being optionally substituted by hydroxy, C₁-C₈-alkyl, C₁-C₈-alkoxyor by a 5- or 6-membered heterocyclic ring having one or more ringhetero atoms selected from the group consisting of oxygen, nitrogen andsulphur,or R¹ is —(C═O)—(NH)_(b)-T where b is 0 or 1 and T denotesC₃-C₈-cycloalkyl or phenyl either of which being optionally substitutedby hydroxy, C₁-C₈-alkyl, C₁-C₈-alkoxy, or by C₁-C₈-alkyl substituted byhydroxy,R² is C₁-C₃-alkyl or halogen;one of R³ and R⁴ is R⁶ and the other is R⁷;R⁵ is hydrogen or halogen;R⁶ is hydrogen, hydroxy, amino, —SOR⁸, —SO₂R⁸, —SO₂NH₂, —SO₂NR⁹R¹⁰,—COR⁸, —CONHR⁸, —NHSO₂R⁸, nitrile, carboxy, —OR⁸ or C₁-C₈-haloalkyl;R⁷ is hydrogen, R¹¹, —OR¹¹, halo, carboxy, —SO₂R⁸, nitrile orC₁-C₈-haloalkyl, or, when R⁴ is R⁷, R⁷ can also be —NR¹²R¹³, R¹⁴ or—OR¹⁴;R⁸ and R¹¹ are independently C₁-C₈-alkyl or C₃-C₈-cycloalkyl, optionallysubstituted by halogen, hydroxy, C₁-C₈-alkoxy, nitrile, amino,C₁-C₈-alkylamino or di(C₁-C₈-alkyl)amino;either R⁹ is C₁-C₈-alkyl or C₃-C₈-cycloalkyl, optionally substituted byhydroxy, C₁-C₈-alkoxy, nitrile, amino, C₁-C₈-alkylamino,di(C₁-C₈-alkyl)amino or a 5- or 6-membered heterocyclic ring having oneor more ring hetero atoms selected from the group consisting of oxygen,nitrogen and sulphur, that ring being optionally substituted byC₁-C₈-alkyl, and R¹⁰ is hydrogen or C₁-C₈-alkyl; or R⁹ and R¹⁰ togetherwith the nitrogen atom to which they are attached form a 5- or6-membered heterocyclic ring that contains one or more further heteroatoms selected from the group consisting of oxygen, nitrogen andsulphur, that ring being optionally substituted by C₁-C₈-alkyl;either R¹² is C₁-C₈-alkyl or C₃-C₈-cycloalkyl optionally substituted byhydroxy, amino, C₁-C₈-alkylamino or di(C₁-C₈-alkyl)amino, and R¹³ ishydrogen or C₁-C₈-alkyl; or R¹² and R¹³ together with the nitrogen atomto which they are attached form a 5- or 6-membered heterocyclic ringthat contains one or more further hetero atoms selected from the groupconsisting of oxygen, nitrogen and sulphur, that ring being optionallysubstituted by C₁-C₈-alkyl; andR¹⁴ is C₁-C₈-alkyl optionally substituted by hydroxy or —NR¹²R¹³.

Terms used in the specification have the following meanings:

“Optionally substituted” as used herein means the group referred to canbe substituted at one or more positions by any one or any combination ofthe radicals listed thereafter.

“Aminocarbonyl” as used herein denotes amino attached through thenitrogen atom to a carbonyl group.

“C₁-C₈-alkyl” denotes straight chain or branched C₁-C₈-alkyl, which maybe, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, straight or branched pentyl, straight or branchedhexyl, straight or branched heptyl, or straight or branched octyl.Preferably, C₁-C₈-alkyl is C₁-C₄-alkyl.

“C₃-C₈-cycloalkyl” denotes cycloalkyl having 3 to 8 ring carbon atoms,for example a monocyclic group such as a cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, any of which can besubstituted by one or more, usually one or two, C₁-C₄-alkyl groups, or abicyclic group such as bicycloheptyl or bicyclooctyl. Preferably“C₃-C₈-cycloalkyl” is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl or cyclooctyl.

“C₁-C₈-alkoxy” denotes straight chain or branched C₁-C₈-alkoxy which maybe, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec-butoxy, tert-butoxy, straight or branched pentoxy,straight or branched hexyloxy, straight or branched heptyloxy, orstraight or branched octyloxy. Preferably, C₁-C₈-alkoxy is C₁-C₄-alkoxy.

“C₁-C₈-haloalkyl” denotes C₁-C₈-alkyl as hereinbefore definedsubstituted by one or more halogen atoms, preferably one, two or threehalogen atoms, preferably fluorine or chlorine atoms. PreferablyC₁-C₈-haloalkyl is C₁-C₄-alkyl substituted by one, two or three fluorineor chlorine atoms.

“C₁-C₈-alkylcarbonyl”, “C₁-C₈-alkoxycarbonyl” and“C₁-C₈-haloalkylcarbonyl” and denote C₁-C₈-alkyl, C₁-C₈-alkoxy orC₁-C₈-haloalkyl respectively as hereinbefore defined attached by acarbon atom to a carbonyl group.

“C₁-C₈-alkylamino” and “di(C₁-C₈-alkyl)amino” denote amino substitutedrespectively by one or two C₁-C₈-alkyl groups as hereinbefore defined,which may be the same or different. Preferably C₁-C₈-alkylamino anddi(C₁-C₈-alkyl)amino are respectively C₁-C₄-alkylamino anddi(C₁-C₄-alkyl)amino.

“C₃-C₈-cycloalkyl” denotes cycloalkyl having 3 to 8 ring carbon atoms,for example a monocyclic group such as a cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, any of which can besubstituted by one or more, usually one or two, C₁-C₄-alkyl groups, or abicyclic group such as bicycloheptyl or bicyclooctyl. Preferably“C₃-C₈-cycloalkyl” is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl or cyclooctyl.

“Halogen” or “halo” may be fluorine, chlorine, bromine or iodine;preferably it is fluorine or chlorine.

“4, 5- or 6-membered heterocyclic ring containing at least one ringheteroatom selected from the group consisting of nitrogen, oxygen andsulphur” as used herein may be, for example, azetidine, furan, pyrrole,pyrrolidine, pyrazole, imidazole, triazole, isotriazole, tetrazole,thiadiazole, isothiazole, oxadiazole, pyridine, oxazole, isoxazole,pyrazine, pyridazine, pyrimidine, piperazine, morpholino, triazine,oxazine or thiazole. Preferred heterocyclic rings include piperazine,morpholino, imidazole, isotriazole, pyrazole, pyridine, furan, oxazole,isoxazole and azetidine.

Throughout this specification and in the claims that follow, unless thecontext requires otherwise, the word “comprise”, or variations such as“comprises” or “comprising”, will be understood to imply the inclusionof a stated integer or step or group of integers or steps but not theexclusion of any other integer or step or group of integers or steps.

Preferred compounds of the present invention include compounds offormula I in free or salt form, wherein

R¹ is hydrogen or aminocarbonyl optionally substituted by nitrile,

or R¹ is C₁-C₈-alkylcarbonyl or C₁-C₈-alkylaminocarbonyl either of whichbeing optionally substituted by halogen, hydroxy, di(C₁-C₈-alkyl)amino,carboxy, C₁-C₈-alkoxycarbonyl, nitrile, phenyl, C₁-C₈-haloalkyl, or byC₁-C₈-alkyl optionally substituted by hydroxy,or R¹ is C₁-C₈-alkylaminocarbonyl optionally substituted byC₃-C₈-cycloalkyl,or R¹ is C₁-C₈-alkylcarbonyl or C₁-C₈-alkylaminocarbonyl either of whichbeing optionally substituted by C₁-C₈-alkoxy optionally substituted byhydroxy,or R¹ is C₁-C₈-alkylcarbonyl or C₁-C₈-alkylaminocarbonyl either of whichbeing optionally substituted by a 5- or 6-membered heterocyclic ringhaving one or more ring hetero atoms selected from the group consistingof oxygen, nitrogen and sulphur, that ring being optionally substitutedby C₁-C₈-alkyl,or R¹ is —(C═O)—(NH)_(a)-Het where a is 0 or 1 and Het denotes a 4-, 5-or 6-membered N-heterocyclic ring having one or more ring hetero atomsselected from the group consisting of oxygen, nitrogen and sulphur, thatring being optionally substituted by hydroxy, C₁-C₈-alkyl, C₁-C₈-alkoxyor by a 5- or 6-membered heterocyclic ring having one or more ringhetero atoms selected from the group consisting of oxygen, nitrogen andsulphur,or R¹ is —(C═O)—NH-T where T denotes C₃-C₈-cycloalkyl or phenyl eitherof which being optionally substituted by hydroxy, C₁-C₈-alkyl, or byC₁-C₈-alkyl substituted by hydroxy,R² is C₁-C₃-alkyl;one of R³ and R⁴ is R⁶ and the other is R⁷;R₅ is hydrogen or halogen;R⁶ is hydrogen, hydroxy, amino, —SO₂R⁸, —SO₂NH₂, —SO₂NR⁹R¹⁰, —NHSO₂R⁸,cyano, carboxy, —OR⁸ or C₁-C₄-haloalkyl;R⁷ is hydrogen, —OR¹¹, fluorine, chlorine, bromine, nitrile orC₁-C₄-haloalkyl, or, when R⁴ is R⁷, R⁷ can also be —NR¹²R¹³ or —OR¹⁴;R⁸ and R¹¹ are independently C₁-C₈-alkyl;either R⁹ is C₁-C₈-alkyl optionally substituted by hydroxy,C₃-C₈-cycloalkyl optionally substituted by hydroxy, C₁-C₈-alkoxy,nitrile, di(C₁-C₈-alkyl)amino or a 5- or 6-membered heterocyclic ringhaving one or more ring hetero atoms selected from the group consistingof oxygen and nitrogen, that ring being optionally substituted byC₁-C₈-alkyl, and R¹⁰ is hydrogen or C₁-C₈-alkyl; or R⁹ and R¹⁰ togetherwith the nitrogen atom to which they are attached form a 5- or6-membered heterocyclic ring that contains one or more further heteroatoms selected from the group consisting of oxygen and nitrogen, thatring being optionally substituted by C₁-C₈-alkyl;either R¹² is C₁-C₈-alkyl optionally substituted bydi(C₁-C₈-alkyl)amino, and R¹³ is hydrogen or C₁-C₈-alkyl; or R¹² and R¹³together with the nitrogen atom to which they are attached form a 5- or6-membered heterocyclic ring that contains one or more further heteroatoms selected from the group consisting of oxygen and nitrogen, thatring being optionally substituted by C₁-C₈-alkyl; andR¹⁴ is C₁-C₈-alkyl.

Further preferred compounds of formula I in free or salt form includethose wherein

R¹ is hydrogen or aminocarbonyl optionally substituted by nitrile,

or R¹ is C₁-C₄-alkylcarbonyl or C₁-C₄-alkylaminocarbonyl either of whichbeing optionally substituted by halogen, hydroxy, di(C₁-C₄-alkyl)amino,carboxy, C₁-C₄-alkoxycarbonyl, nitrile, phenyl, C₁-C₄-haloalkyl, or byC₁-C₄-alkyl optionally substituted by hydroxy,or R¹ is C₁-C₄-alkylaminocarbonyl optionally substituted byC₃-C₈-cycloalkyl,or R¹ is C₁-C₄-alkylcarbonyl or C₁-C₄-alkylaminocarbonyl either of whichbeing optionally substituted by C₁-C₄-alkoxy optionally substituted byhydroxy,or R¹ is C₁-C₄-alkylcarbonyl or C₁-C₄-alkylaminocarbonyl either of whichbeing optionally substituted by a 5- or 6-membered heterocyclic ringhaving one or more ring hetero atoms selected from the group consistingof oxygen, nitrogen and sulphur, that ring being optionally substitutedby C₁-C₄-alkyl,or R¹ is —(C═O)—(NH)_(a)-Het where a is 0 or 1 and Het denotes a 4-, 5-or 6-membered N-heterocyclic ring having one or more ring hetero atomsselected from the group consisting of oxygen, nitrogen and sulphur, thatring being optionally substituted by hydroxy, C₁-C₄-alkyl, C₁-C₄-alkoxyor by a 5- or 6-membered heterocyclic ring having one or more ringhetero atoms selected from the group consisting of oxygen, nitrogen andsulphur,or R¹ is —(C═O)—NH-T where T denotes C₃-C₈-cycloalkyl or phenyl eitherof which being optionally substituted by hydroxy, C₁-C₄-alkyl, or byC₁-C₄-alkyl substituted by hydroxy,R² is C₁-C₃-alkyl;one of R³ and R⁴ is R⁶ and the other is R⁷;R⁵ is hydrogen or halogen;R⁶ is hydrogen, hydroxy, amino, SO₂R⁸, SO₂NH₂, SO₂NR⁹R¹⁰, NHSO₂R⁸,nitrile, carboxy, OR⁸ or C₁-C₄-haloalkyl;R⁷ is hydrogen, —OR¹¹, fluorine, chlorine, bromine, cyano orC₁-C₄-haloalkyl, or, when R⁴ is R⁷, R⁷ can also be —NR¹²R¹³ or —OR¹⁴;R⁸ and R¹¹ are independently C₁-C₄-alkyl;either R⁹ is C₁-C₄-alkyl optionally substituted by hydroxy,C₃-C₈-cycloalkyl optionally substituted by hydroxy, C₁-C₄-alkoxy,nitrile, di(C₁-C₄-alkyl)amino or a 5- or 6-membered heterocyclic ringhaving one or more ring hetero atoms selected from the group consistingof oxygen and nitrogen, that ring being optionally substituted byC₁-C₄-alkyl, and R¹⁰ is hydrogen or C₁-C₄-alkyl; or R⁹ and R¹⁰ togetherwith the nitrogen atom to which they are attached form a 5- or6-membered heterocyclic ring that contains one or more further heteroatoms selected from the group consisting of oxygen and nitrogen, thatring being optionally substituted by C₁-C₄-alkyl;either R¹² is C₁-C₄-alkyl optionally substituted bydi(C₁-C₄-alkyl)amino, and R¹³ is hydrogen or C₁-C₄-alkyl; or R¹² and R¹³together with the nitrogen atom to which they are attached form a 5- or6-membered heterocyclic ring that contains one or more further heteroatoms selected from the group consisting of oxygen and nitrogen, thatring being optionally substituted by C₁-C₄-alkyl; andR¹⁴ is C₁₋₄ alkyl.

In a second aspect, the present invention provides compounds of formulaI in free or salt form, wherein

R¹ is hydrogen, or R¹ is aminocarbonyl, C₁-C₈-alkylcarbonyl orC₁-C₈-alkylaminocarbonyl either of which being optionally substituted byhydroxy, amino, C₁-C₈-alkylamino, di(C₁-C₈-alkyl(amino), carboxy,C₁-C₈-alkyl optionally substituted by hydroxy, halogen, C₃-C₈-cycloalkyloptionally substituted by hydroxy, C₁-C₈-alkoxy optionally substitutedby hydroxy, C₁-C₈-alkoxycarbonyl, nitrile, halogen, phenyl optionallysubstituted by hydroxy or C₁-C₈-alkyl, or a 5- or 6-memberedheterocyclic ring having one or more ring hetero atoms selected from thegroup consisting of oxygen, nitrogen and sulphur, that ring beingoptionally substituted by hydroxy, C₁-C₈-alkyl or C₁-C₈-alkoxy, or R¹ is—(C═O)—(NH)_(a)-Het where a is 0 or 1 and Het denotes a 5- or 6-memberedheterocyclic ring having one or more ring hetero atoms selected from thegroup consisting of oxygen, nitrogen and sulphur, that ring beingoptionally substituted by hydroxy, C₁-C₈-alkyl or C₁-C₈-alkoxy;R² is C₁-C₃-alkyl or halogen;one of R³ and R⁴ is R⁶ and the other is R⁷;R⁵ is hydrogen or halogen;R⁶ is hydrogen, hydroxy, amino, —SOR⁸, —SO₂R⁸, —SO₂NH₂, —SO₂NR⁹R¹⁰,—COR⁸, —CONHR⁸, —NHSO₂R⁸, nitrile, carboxy, —OR⁸ or C₁-C₈-haloalkyl;R⁷ is hydrogen, R¹¹, —OR¹¹, halo, carboxy, —SO₂R⁸, cyano orC₁-C₈-haloalkyl, or, when R⁴ is R⁷, R⁷ can also be —NR¹²R¹³, R¹⁴ or—OR¹⁴;R⁸ and R¹¹ are independently C₁-C₈-alkyl or C₃-C₈-cycloalkyl, optionallysubstituted by halogen, hydroxy, C₁-C₈-alkoxy, nitrile, amino,C₁-C₈-alkylamino or di(C₁-C₈-alkyl)amino;either R⁹ is C₁-C₈-alkyl or C₃-C₈-cycloalkyl, optionally substituted byhydroxy, C₁-C₈-alkoxy, nitrile, amino, C₁-C₈-alkylamino,di(C₁-C₈-alkyl)amino or a 5- or 6-membered heterocyclic ring having oneor more ring hetero atoms selected from the group consisting of oxygen,nitrogen and sulphur, that ring being optionally substituted byC₁-C₈-alkyl, and R¹⁰ is hydrogen or C₁-C₈-alkyl; or R⁹ and R¹⁰ togetherwith the nitrogen atom to which they are attached form a 5- or6-membered heterocyclic ring that contains one or more further heteroatoms selected from the group consisting of oxygen, nitrogen andsulphur, that ring being optionally substituted by C₁-C₈-alkyl;either R¹² is C₁-C₈-alkyl or C₃-C₈-cycloalkyl optionally substituted byhydroxy, amino, C₁-C₈-alkylamino or di(C₁-C₈-alkyl)amino, and R¹³ ishydrogen or C₁-C₈-alkyl; or R¹² and R¹³ together with the nitrogen atomto which they are attached form a 5- or 6-membered heterocyclic ringthat contains one or more further hetero atoms selected from the groupconsisting of oxygen, nitrogen and sulphur, that ring being optionallysubstituted by C₁-C₈-alkyl; andR¹⁴ is C₁-C₈-alkyl optionally substituted by hydroxy or —NR¹²R¹³.

Preferred compounds include compounds of formula I wherein

R¹ is hydrogen, or R¹ is aminocarbonyl, C₁-C₈-alkylcarbonyl orC₁-C₈-alkylaminocarbonyl either of which being optionally substituted byhydroxy, di(C₁-C₈-alkylamino), carboxy, C₁-C₈-alkyl optionallysubstituted by hydroxy, halogen, C₃-C₈-cycloalkyl optionally substitutedby hydroxy, C₁-C₈-alkoxy optionally substituted by hydroxy,C₁-C₈-alkoxycarbonyl, nitrile, halogen, phenyl optionally substituted byhydroxy or C₁-C₈-alkyl, or a 5- or 6-membered heterocyclic ring havingone or more ring hetero atoms selected from the group consisting ofoxygen, nitrogen and sulphur, that ring being optionally substituted byC₁-C₈-alkyl or C₁-C₈-alkoxy, or R¹ is —(C═O)—(NH)_(a)-Het where a is 0or 1 and Het denotes a 5- or 6-membered N-heterocyclic ring optionallysubstituted by hydroxy, C₁-C₈-alkyl or C₁-C₈-alkoxy;R² is C₁-C₃-alkyl;one of R³ and R⁴ is R⁶ and the other is R⁷;R⁵ is hydrogen or halogen;R⁶ is hydrogen, hydroxy, amino, —SO₂R⁸, —SO₂NH₂, —SO₂NR⁹R¹⁰, —NHSO₂R⁸,cyano, carboxy, —OR⁸ or C₁-C₄-haloalkyl;R⁷ is hydrogen, —OR¹¹, fluorine, chlorine, bromine, cyano orC₁-C₄-haloalkyl, or, when R⁴ is R⁷, R⁷ can also be —NR¹²R¹³ or —OR¹⁴;R⁸ and R¹¹ are independently C₁-C₈-alkyl;either R⁹ is C₁-C₈-alkyl optionally substituted by hydroxy,C₃-C₈-cycloalkyl optionally substituted by hydroxy, C₁-C₈-alkoxy,nitrile, di(C₁-C₈-alkyl)amino or a 5- or 6-membered heterocyclic ringhaving one or more ring hetero atoms selected from the group consistingof oxygen and nitrogen, that ring being optionally substituted byC₁-C₈-alkyl, and R¹⁰ is hydrogen or C₁-C₈-alkyl; or R⁹ and R¹⁰ togetherwith the nitrogen atom to which they are attached form a 5- or6-membered heterocyclic ring that contains one or more further heteroatoms selected from the group consisting of oxygen and nitrogen, thatring being optionally substituted by C₁-C₈-alkyl;either R¹² is C₁-C₈-alkyl optionally substituted bydi(C₁-C₈-alkyl)amino, and R¹³ is hydrogen or C₁-C₈-alkyl; or R¹² and R¹³together with the nitrogen atom to which they are attached form a 5- or6-membered heterocyclic ring that contains one or more further heteroatoms selected from the group consisting of oxygen and nitrogen, thatring being optionally substituted by C₁-C₈-alkyl; andR¹⁴ is C₁-C₈-alkyl.

In a third aspect, the present invention provides compounds of formula Iin free or salt form, wherein

R¹ is hydrogen, or C₁-C₈-alkylcarbonyl or C₁-C₈-alkylaminocarbonyloptionally substituted by amino, carboxy, C₁-C₈-alkoxy,C₁-C₈-alkoxycarbonyl, nitrile, halogen or a 5 or 6-membered heterocyclicring having one or more ring hetero atoms selected from the groupconsisting of oxygen, nitrogen and sulphur, that ring being optionallysubstituted by C₁-C₈-alkyl;R² is C₁-C₃-alkyl or halogen;one of R³ and R⁴ is R⁶ and the other is R⁷;R⁵ is hydrogen or halogen;R⁶ is hydrogen, hydroxy, amino, SOR⁸, SO₂R⁸, SO₂NH₂, SO₂NR⁹R¹⁰, COR⁸,CONHR⁸, NHSO₂R⁸, nitrile, carboxy, OR⁸ or C₁-C₈-haloalkyl;R⁷ is hydrogen, R¹¹, OR¹¹, halo, cyano, carboxy, SO₂R⁸, orC₁-C₈-haloalkyl, or, when R⁴ is R⁷, R⁷ can also be NR¹²R¹³, R¹⁴ or OR¹⁴;R⁸ and R¹¹ are independently C₁-C₈-alkyl or C₃-C₈-cycloalkyl, optionallysubstituted by halogen, hydroxy, C₁-C₈-alkoxy, nitrile, amino,C₁-C₈-alkylamino or di(C₁-C₈-alkyl)amino; either R⁹ is C₁-C₈-alkyl orC₃-C₈-cycloalkyl, optionally substituted by hydroxy, C₁-C₈-alkoxy,nitrile, amino, C₁-C₈-alkylamino, di(C₁-C₈-alkyl)amino or a 5 or6-membered heterocyclic ring having one or more ring hetero atomsselected from the group consisting of oxygen, nitrogen and sulphur, thatring being optionally substituted by C₁-C₈-alkyl, and R¹⁰ is hydrogen orC₁-C₈-alkyl; or R⁹ and R¹⁰ together with the nitrogen atom to which theyare attached form a 5 or 6-membered heterocyclic ring that contains oneor more further hetero atoms selected from the group consisting ofoxygen, nitrogen and sulphur, that ring being optionally substituted byC₁-C₈-alkyl;either R¹² is C₁-C₈-alkyl or C₃-C₈-cycloalkyl optionally substituted byhydroxy, amino, C₁-C₈-alkylamino or di(C₁-C₈-alkyl)amino, and R¹³ ishydrogen or C₁-C₈-alkyl; or R¹² and R¹³ together with the nitrogen atomto which they are attached form a 5 or 6-membered heterocyclic ring thatcontains one or more further hetero atoms selected from the groupconsisting of oxygen, nitrogen and sulphur, that ring being optionallysubstituted by C₁-C₈-alkyl; andR¹⁴ is C₁-C₈-alkyl optionally substituted by hydroxy or NR¹²R¹³.

Preferred compounds include compounds of formula I, wherein

R¹ is hydrogen, C₁-C₈-alkylcarbonyl, C₁-C₈-alkylaminocarbonyl optionallysubstituted by carboxy or C₁-C₈-alkoxycarbonyl;

R² is C₁-C₃-alkyl;

one of R³ and R⁴ is R⁶ and the other is R⁷;

R⁵ is hydrogen or halogen;

R⁶ is hydrogen, hydroxy; amino, SO₂R⁸, SO₂NH₂, SO₂NR⁹R¹⁰, NHSO₂R⁸,cyano, carboxy, OR⁸ or C₁-C₄-haloalkyl;

R⁷ is hydrogen, OR¹¹, fluorine, chlorine, bromine, cyano orC₁-C₄-haloalkyl, or, when R⁴ is R⁷, R⁷ can also be NR¹²R¹³ or OR¹⁴;

R⁸ and R¹¹ are independently C₁-C₈-alkyl;

either R⁹ is C₁-C₈-alkyl or C₃-C₈-cycloalkyl, optionally substituted byhydroxy, C₁-C₈-alkoxy, nitrile, di(C₁-C₈-alkyl)amino or a 5 or6-membered heterocyclic ring having one or more ring hetero atomsselected from the group consisting of oxygen and nitrogen, that ringbeing optionally substituted by C₁-C₈-alkyl, and R¹⁰ is hydrogen orC₁-C₈-alkyl; or R⁹ and R¹⁰ together with the nitrogen atom to which theyare attached form a 5 or 6-membered heterocyclic ring that contains oneor more further hetero atoms selected from the group consisting ofoxygen and nitrogen, that ring being optionally substituted byC₁-C₈-alkyl;either R¹² is C₁-C₈-alkyl optionally substituted bydi(C₁-C₈-alkyl)amino, and R¹³ is hydrogen or C₁-C₈-alkyl; or R¹² and R¹³together with the nitrogen atom to which they are attached form a 5 or6-membered heterocyclic ring that contains one or more further heteroatoms selected from the group consisting of oxygen and nitrogen, thatring being optionally substituted by C₁-C₈-alkyl; andR¹⁴ is C₁-C₈-alkyl.

Many of the compounds represented by formula I are capable of formingacid addition salts, particularly pharmaceutically acceptable acidaddition salts. Pharmaceutically acceptable acid addition salts of thecompound of formula I include those of inorganic acids, for example,hydrohalic acids such as hydrofluoric acid, hydrochloric acid,hydrobromic acid or hydroiodic acid, nitric acid, sulfuric acid,phosphoric acid; and organic acids, for example aliphatic monocarboxylicacids such as formic acid, acetic acid, trifluoroacetic acid, propionicacid and butyric acid, aliphatic hydroxy acids such as lactic acid,citric acid, tartaric acid or malic acid, dicarboxylic acids such asmaleic acid or succinic acid, aromatic carboxylic acids such as benzoicacid, p-chlorobenzoic acid, diphenylacetic acid or triphenylacetic acid,aromatic hydroxy acids such as o-hydroxybenzoic acid, p-hydroxybenzoicacid, 1-hydroxynaphthalene-2-carboxylic acid or3-hydroxynaphthalene-2-carboxylic acid, and sulfonic acids such asmethanesulfonic acid or benzenesulfonic acid. These salts may beprepared from compounds of formula I by known salt-forming procedures.

Compounds of formula I which contain acidic, e.g. carboxyl, groups, arealso capable of forming salts with bases, in particular pharmaceuticallyacceptable bases such as those well known in the art; suitable suchsalts include metal salts, particularly alkali metal or alkaline earthmetal salts such as sodium, potassium, magnesium or calcium salts, orsalts with ammonia or pharmaceutically acceptable organic amines orheterocyclic bases such as ethanolamines, benzylamines or pyridine.These salts may be prepared from compounds of formula I by knownsalt-forming procedures.

In those compounds where there is an asymmetric carbon atom thecompounds exist in individual optically active isomeric forms or asmixtures thereof, e.g. as racemic or diastereomeric mixtures. Thepresent invention embraces both individual optically active R and Sisomers as well as mixtures, e.g. racemic or diastereomeric mixtures,thereof.

Specific preferred compounds of formula I are described hereinafter inthe Examples.

The invention provides, in another aspect, a process for preparing acompound of formula I in free or salt form which comprises the steps of:

-   (i) (A) for the preparation of compounds of formula I where R¹ is    C₁-C₈-alkylcarbonyl, C₁-C₈-alkylaminocarbonyl optionally substituted    by amino, carboxy, C₁-C₈-alkoxy, C₁-C₈-alkoxycarbonyl, nitrile or    halogen, or a 5 or 6-membered heterocyclic ring having one or more    ring hetero atoms selected from the group consisting of oxygen,    nitrogen and sulphur, that ring being optionally substituted by    C₁-C₈-alkyl, reacting a compound of formula II

-   -   wherein R¹ and R² are as hereinbefore defined, with a compound        of formula III

-   -   wherein R³, R⁴ and R⁵ are as hereinbefore defined, in the        presence of a transition metal catalyst, preferably palladium;    -   (B) for the preparation of compounds of formula I where R³ or R⁴        is —SO₂NH₂ or —SO₂NR⁹R¹⁰, reacting a compound of formula IV

-   -   wherein R¹, R², R⁵ and R⁷ are as hereinbefore defined and the        —SO₂Cl group is meta or para to the thiazole ring, with ammonia        or a compound of formula R⁹R¹⁰NH;    -   (C) for the preparation of compounds of formula I where R³ or R⁴        is NHSO₂R⁸, reacting a compound of formula I where one or R³ and        R⁴ is NH₂ with a sulfonyl chloride of formula R⁸SO₂Cl;    -   (D) for the preparation of compounds of formula I where R⁴ is        NR¹²R¹³, reacting a compound of formula I where R⁴ is halogen        and R³ is SO₂R⁸ with a compound of formula V

-   -   where R¹² and R¹³ are as hereinbefore defined;    -   (E) for the preparation of compounds of formula I where R¹ is        optionally substituted C₁-C₈-alkylaminocarbonyl, reacting a        compound of formula I where R¹ is hydrogen with a compound of        formula VI        R⁵—N═C═O  VI    -   R¹⁵—N═C═O, wherein R¹⁵ is C₁-C₈-alkyl optionally substituted by        carboxy or C₁-C₈-alkoxycarbonyl;    -   (F) for the preparation of compounds of formula I where one of        R³ and R⁴ is amino and the other is hydrogen or halogen and at        least one of R³, R⁴ and R⁵ is halogen, halogenating a compound        of formula I where R³ or R⁴ is amino and the other is hydrogen;    -   (G) reacting a compound of formula VII

-   -   wherein R², R³, R⁴ and R⁵ are as hereinbefore defined and X is        halogen, with a compound of formula VIII

-   -   wherein R¹ is as hereinbefore defined;    -   (H) for the preparation of compounds of formula I where R³ or R⁴        is —SO₂R⁸ and R⁸ is methyl, reacting a compound of formula IV        wherein R¹, R², R⁵ and R⁷ are as hereinbefore defined and the        —SO₂Cl group is meta or para to the thiazolyl ring, with an        alkali metal sulphite and an alkali metal bicarbonate, followed        by reaction with bromoacetic acid or an alkyl halide, e.g.        iodomethane at elevated temperature;    -   (I) for the preparation of compounds of formula I where R¹ is        C₁-C₈-alkylamino-carbonyl optionally substituted by a 5- or        6-membered heterocyclic ring having one or more ring hetero        atoms selected from the group consisting of oxygen, nitrogen and        sulphur, that ring being optionally substituted by C₁-C₈-alkyl        or C₁-C₈-alkoxy, or where R¹ is —(C═O)—(NH)_(a)-Het where a is 0        and Het denotes a 4-, 5- or 6-membered heterocyclic ring having        one or more ring hetero atoms selected from the group consisting        of oxygen, nitrogen and sulphur, that ring being optionally        substituted by hydroxy, C₁-C₈-alkyl, C₁-C₈-alkoxy or by a 5- or        6-membered heterocyclic ring having one or more ring hetero        atoms selected from the group consisting of oxygen, nitrogen and        sulphur,    -   or where R¹ is —(C═O)—(NH)_(b)-T where b is 0 and T denotes        C₃-C₈-cycloalkyl or phenyl either of which being optionally        substituted by hydroxy, C₁-C₈-alkyl, C₁-C₈-alkoxy, or by        C₁-C₈-alkyl substituted by hydroxy,    -   reacting a compound of formula I where R¹ is hydrogen with a        compound of formula IX

-   -   where R¹⁶ is C₁-C₈-alkyl substituted by a 5- or 6-membered        heterocyclic ring having one or more ring hetero atoms selected        from the group consisting of oxygen, nitrogen and sulphur, that        ring being optionally substituted by C₁-C₈-alkyl or        C₁-C₈-alkoxy, or R¹⁶ is a 4-, 5- or 6-membered heterocyclic ring        having one or more ring hetero atoms selected from the group        consisting of oxygen, nitrogen and sulphur, that ring being        optionally substituted by hydroxy, C₁-C₈-alkyl, C₁-C₈-alkoxy or        by a 5- or 6-membered heterocyclic ring having one or more ring        hetero atoms selected from the group consisting of oxygen,        nitrogen and sulphur,    -   or R¹⁶ is C₃-C₈-cycloalkyl or phenyl either of which being        optionally substituted by hydroxy, C₁-C₈-alkyl, C₁-C₈-alkoxy, or        by C₁-C₈-alkyl substituted by hydroxy;    -   (J) for the preparation of compounds of formula I where R¹ is        C₁-C₈-alkylaminocarbonyl optionally substituted by halogen,        hydroxy, amino, C₁-C₈-alkylamino, di(C₁-C₈-alkyl)amino, carboxy,        C₁-C₈-alkoxycarbonyl, nitrile, phenyl, C₁-C₈-haloalkyl, or by        C₁-C₈-alkyl optionally substituted by hydroxy,    -   or R¹ is C₁-C₈-alkylaminocarbonyl optionally substituted by        C₃-C₈-cycloalkyl optionally substituted by hydroxy,    -   or R¹ is C₁-C₈-alkylaminocarbonyl optionally substituted by        C₁-C₈-alkoxy optionally substituted by hydroxy,    -   or R¹ is C₁-C₈-alkylaminocarbonyl optionally substituted by        phenyl optionally substituted by hydroxy or C₁-C₈-alkyl,    -   or R¹ is C₁-C₈-alkylaminocarbonyl optionally substituted by a 5-        or 6-membered heterocyclic ring having one or more ring hetero        atoms selected from the group consisting of oxygen, nitrogen and        sulphur, that ring being optionally substituted by hydroxy,        C₁-C₈-alkyl or C₁-C₈-alkoxy,    -   or R¹ is —(C═O)—(NH)_(a)-Het where a is 1 and Het denotes a 4-,        5- or 6-membered heterocyclic ring having one or more ring        hetero atoms selected from the group consisting of oxygen,        nitrogen and sulphur, that ring being optionally substituted by        hydroxy, C₁-C₈-alkyl, C₁-C₈-alkoxy or by a 5- or 6-membered        heterocyclic ring having one or more ring hetero atoms selected        from the group consisting of oxygen, nitrogen and sulphur,    -   or R¹ is —(C═O)—(NH)_(b)-T where b is 1 and T denotes        C₃-C₈-cycloalkyl or phenyl either of which being optionally        substituted by hydroxy, C₁-C₈-alkyl, C₁-C₈-alkoxy, or by        C₁-C₈-alkyl substituted by hydroxy,    -   reacting a compound of formula X

-   -   wherein R², R³, R⁴ and R⁵ are as hereinbefore defined, with a        compound of formula XI

-   -   where R¹⁷ and R¹⁸ are selected from hydrogen, hydroxy, amino,        C₁-C₈-alkylamino, di(C₁-C₈-alkyl(amino), carboxy, C₁-C₈-alkyl        optionally substituted by hydroxy, halogen, C₃-C₈-cycloalkyl        optionally substituted by hydroxy, C₁-C₈-alkoxy optionally        substituted by hydroxy, C₁-C₈-alkoxycarbonyl, nitrile, halogen,        phenyl optionally substituted by hydroxy or C₁-C₈-alkyl, and a        5- or 6-membered heterocyclic ring having one or more ring        hetero atoms selected from the group consisting of oxygen,        nitrogen and sulphur, that ring being optionally substituted by        hydroxy, C₁-C₈-alkyl or C₁-C₈-alkoxy,    -   or when R¹ is —(C═O)—(NH)_(a)-Het, R¹⁷ is hydrogen and R¹⁸ is a        4-, 5- or 6-membered heterocyclic ring having one or more ring        hetero atoms selected from the group consisting of oxygen,        nitrogen and sulphur, that ring being optionally substituted by        hydroxy, C₁-C₈-alkyl, C₁-C₈-alkoxy or by a 5- or 6-membered        heterocyclic ring having one or more ring hetero atoms selected        from the group consisting of oxygen, nitrogen and sulphur,    -   or when R¹ is —(C═O)—(NH)_(b)—T R¹⁷ is hydrogen and R₁₈ is        C₃-C₈-cycloalkyl or phenyl either of which being optionally        substituted by hydroxy, C₁-C₈-alkyl, C₁-C₈-alkoxy, or by        C₁-C₈-alkyl substituted by hydroxy; or    -   (K) the preparation of compounds of formula I where R¹ is        hydrogen, hydrolysing a compound of formula I where R¹ is        C₁-C₈-alkylcarbonyl; and

-   (ii) recovering the resultant compound of formula I in free or salt    form.

Process variant (A) may be carried out using known Suzuki reactionprocedures, or analogously, e.g. as hereinafter described in theExamples. It may be carried out in an organic solvent such asdimethoxyethane (DME) usually in the presence of aqueous alkali metalcarbonate. The reaction temperature may be from room temperature to 100°C., but conveniently 80° C. The palladium catalyst may be, for example,a bis(triarylphosphine) palladium halide.

Process variant (B) may be carried out using known procedures forpreparation of sulphonamides from sulfonyl chlorides, or analogously,e.g. as hereinafter described in the Examples. It may be carried out inan aqueous solvent or an organic solvent, e.g. an ether such as dioxane,usually in the presence of an alkali metal carbonate. The reactiontemperature may be from 0° C. to 100° C., but conveniently roomtemperature.

Process variant (C) may be carried out using known procedures forreaction of amines with sulfonyl chlorides, or analogously, e.g. ashereinafter described in the Examples. It may be carried out in anorganic solvent, e.g. dimethylformamide (DMF), usually in the presenceof an alkali metal carbonate. The reaction temperature may be from 0° C.to 100° C., but conveniently room temperature.

Process variant (D) may be carried out using known procedures forreaction of aryl halides, ortho to an electron withdrawing group, withprimary or secondary amines, or analogously, e.g. as hereinafterdescribed in the Examples. It may be carried out either neat or in anorganic solvent, e.g. dimethylsulphoxide. The reaction temperature maybe from 100° C. to 170° C. but conveniently about 120° C. to 140° C.

Process variant (E) may be carried out using known procedures forreaction of amines with acylating agents or isocyanates, or analogously,e.g. as hereinafter described in the Examples. It may be carried out inan organic solvent, e.g. dimethylformamide. The reaction temperature maybe from 0° C. to 100° C., but conveniently room temperature.

Process variant (F) may be carried out using known procedures forhalogenating anilines, or analogously, e.g. as hereinafter described inthe Examples. Chlorination may be carried out using hydrogen peroxide,acetic acid and hydrochloric acid, for example as described in S.Mukhopadhyay, K. H. Chandnani and S. B. Chandalia, Organic ProcessResearch & Development, 1999, 3, 196-200. The reaction temperature maybe from 0° C. to 50° C., but conveniently room temperature.Mono-bromination may be carried out by reaction with N-bromosuccinimide(NBS) in an organic solvent, preferably dimethylsulphoxide. But mono- ordi-bromination may be carried out by reaction with bromine in an organicsolvent, e.g. an ether such as dioxane. In both cases the reaction thereaction temperature may be from 0° C. to 50° C., but conveniently roomtemperature.

Process variant (G) may be carried out using known procedures forpreparing aminothiazoles, or analogously, e.g. as hereinafter describedin the Examples. The halogen X is preferably bromine. The reaction maybe carried out in an organic solvent, e.g. an alcohol such as ethanol.The reaction temperature may be from room temperature to the refluxtemperature of the solvent, but conveniently from about 50° C. to 60° C.

Process variant (H) may be carried out using the procedure known in R.W. Brown, Journal of Organic Chemistry, 1991, 56, 4974 for convertingsulfonyl halides to sulfones, or analogously, e.g. as hereinafterdescribed in the Examples. It may be carried out with the alkali metalsulphite, e.g. sodium sulphite, and the alkali metal bicarbonate, e.g.sodium bicarbonate in water at a temperature from 20° C. to 100° C., butconveniently at about 75° C. The reaction with bromoacetic acid may becarried out at temperature from 50° C. to 150° C., but conveniently atabout 100° C. An alkyl halide, e.g. iodomethane may be used in place ofbromoacetic acid

Process variant (I) may be carried out using known procedures forreacting amines with carboxylic acids, or analogously, e.g. ashereinafter described in the Examples. The reaction may be carried outin an organic solvent, e.g. dichloromethane, in the presence of acoupling agent, e.g. HATU, and a base, e.g. triethylamine. The reactiontemperature may be from 0° C. to 50° C., but conveniently roomtemperature.

Process variant (J) may be carried out using known procedures forreacting isocyanates with amines, or analogously, e.g. as hereinafterdescribed in the Examples. The reaction may be carried out in an organicsolvent, e.g. dioxane or DMF. The reaction temperature may be anelevated temperature, for example from 50° C. to 100° C., but preferablyabout 80° C.

Process variant (K) may be carried out using known procedures forconverting alkylcarbonylamines to amines, or analogously, e.g. ashereinafter described in the Examples. The reaction may be carried outin an organic solvent, e.g. ethanol, in the presence of a base,preferably a strong base such as sodium hydroxide. The reactiontemperature may be an elevated temperature, for example from 50° C. to100° C., but preferably about 90° C.

The compounds of formula I in free or salt form can be recovered fromreaction mixtures and purified in a conventional manner. Isomer mixturescan be separated into individual isomers, e.g. enantiomers, in aconventional manner, e.g. by fractional crystallisation.

Compounds of formula II may be prepared by the method known in Garreau,Bull. Soc. Chim. Fr, 1954,1048, or analogously, e.g. as hereinafterdescribed in the Examples.

Compounds of formula III are commercially available.

Compounds of formula IV may be prepared by reacting a compound offormula XII

wherein R¹, R², R⁵ and R⁷ are as hereinbefore defined, with nitrous acidto give a diazo compound which is then reacted with sulphur dioxide inthe presence of copper chloride, for example by the method described inE. E. Gilbert, Synthesis 1969, 1-10, to give the corresponding sulfonylchloride of formula IV.

Compounds of formula IV may also be prepared by reacting a compound offormula XIII

wherein R¹, R², R⁵ are as hereinbefore defined and R⁷ is halogen or OR¹¹with chlorosulfonic acid, or analogously, e.g. as described in theExamples.

Compounds of formula V are either available commercially or may beprepared by known methods.

Compounds of formula VI are either available commercially or may beprepared by known methods.

Compounds of formula VII may be prepared by reacting a compound offormula XIV

wherein R², R³, R⁴ and R⁵ are as hereinbefore defined, with anhalogenating agent, for example bromine, or analogously, e.g. asdescribed in the Examples.

Compounds of formula VIII are commercially available or may be preparedby known methods.

Compounds of formula IX are commercially available or may be prepared byknown methods.

Compounds of formula X may be prepared by reacting a compound of formulaI wherein R¹ is hydrogen with phosgene or analogously, e.g. as describedin the Examples.

Compounds of formula XI are commercially available or may be prepared byknown methods.

Compounds of formula XII may be prepared by reduction of compounds offormula XV

wherein R¹, R², R⁵ and R⁷ are as hereinbefore defined, using standardtechniques known for the reduction of aromatic nitro compounds toanilines, for example catalytic hydrogenation using a transition metalcatalyst, preferably palladium on carbon, in an organic solvent, e.g.ethyl acetate, under an atmosphere of hydrogen.

Compounds of formula XIII may be prepared by reacting the correspondingketone of formula XVI

wherein R², R³, R⁴ and R⁵ are as hereinbefore defined and X is halogen,with a compound of formula VIII wherein R¹ is as hereinbefore defined,or analogously, e.g. as described in the Examples.

Compounds of formula XIV where either R³ or R⁴ is independently SO₂NH₂or SO₂NR⁹R¹⁰ may be prepared by reacting a compound of formula XII whereR¹ and R² are as hereinbefore defined and one of R¹ or R⁷ is hydrogen,the other being halogen or OR¹¹, with chlorosulfonic acid followed bytreatment with an amine or ammonia, or analogously, e.g. as described inthe Examples.

Compounds of formula XIV may also be obtained from commerciallyavailable compounds of formula XVII

by known methods, for example as described in R. V. Heinzelman, OrganicSynthesis 1963, IV, 573.

Compounds of formula XV may be prepared as described in process variant(G) or by known procedures, for example as described in J. Liebscher, E.Mitzner, Synthesis, 1985, 4, 414-417.

Compounds of formula XVI may be prepared by reacting a compound offormula XVIII

wherein R², R⁵, and R⁷ are as hereinbefore defined, with an halogenatingagent, for example bromine, or analogously, e.g. as described in theExamples.

Compounds of formula XVII where R³ is SO₂CH₃ are available fromcommercial sources or may be prepared from compounds of formula XVIwhere R³ is halogen, for example by the method described in A. Ulman andE. Urankar, J. Org. Chem., 1989, 54, p 4691-4692.

Compounds of formula XVIII are commercially available or may be preparedby known methods.

Compounds of formula I in free form may be converted into salt form, andvice versa, in a conventional manner. The compounds in free or salt formcan be obtained in the form of hydrates or solvates containing a solventused for crystallization. Compounds of formula I can be recovered fromreaction mixtures and purified in a conventional manner. Isomers, suchas enantiomers, may be obtained in a conventional manner, e.g. byfractional crystallization or asymmetric synthesis from correspondinglyasymmetrically substituted, e.g. optically active, starting materials.

Compounds of formula I and their pharmaceutically acceptable salts,hereinafter referred to alternatively as agents of the invention, areuseful as pharmaceuticals. In particular, they exhibit inhibition ofphosphatidylinositol 3-kinase (Pi3 kinase) enzymes, especially the gammaisoform (p110γ), which are responsible for generating phosphorylatedsignalling products. The inhibitory properties of compounds of formula Imay be demonstrated in the following test procedures:

Baculovirus expressing different fragments of PI3Kγ fused to GST havebeen previously described by Stoyanova, S., Bulgarelli-Leva, G., Kirsch,C., Hanck, T., Klinger, R., Wetzker, R., Wymann, M. P. (1997) Lipid- andprotein kinase activities of G protein-coupled PI 3-kinase g:structure-activity analysis and interactions with wortmannin. Biochem.J., 324:489. Residues 38-1102 of human PI3Kγ are subcloned into theBamH1 and EcoR1 sites of the transfer vector pAcG2T (Pharmingen) tocreate a GST-PI3Kγ lacking the first 37 residues of PI3Kγ. To expressthe recombinant protein, Sf9 (Spodoptera frugiperda 9) insect cells areroutinely maintained at densities between 3×10⁵ and 3×10⁶ cells/ml inserum containing TNMFH medium (Sigma). Sf9 cells, at a density of 2×10⁶are infected with human GST-PI3KγΔ34 baculovirus at a multiplicity ofinfection (m.o.i.) of 1 for 72 hours. The infected cells are harvestedby centrifugation at 1400 g for 4 minutes at 4° C. and the cell pelletsare frozen at −80° C. Both Sf9 and Sf21 cells work equally well. Sf9cells (1×10⁹) are resuspended in 100 ml cold (4° C.) lysis buffer (50 mMTris-HCl pH 7.5, 1% Triton X-100, 150 mM NaCl, 1 mM NaF, 2 mM DTT andprotease inhibitors. Cells are incubated on ice for 30 minutes thencentrifuged at 15000 g for 20 minutes at 4° C. Purification of thesupernatant sample is carried out at 4° C. by affinity chromatographyusing SEPHAROSE™ agarose gel beads coupled to glutathione (from AmershamPharmacia Biotech). A cell lysate/GST resin ratio of 50:1 is used. TheGST resin is firstly pre-rinsed to remove ethanol preservative and thenequilibrated with lysis buffer. Cell lysate (supernatant) is added(usually as 50 ml lysate to 1 ml GST resin in 50 ml tubes) and gentlyrotated on a mixer at 4° C. for 2-3 hours. The unbound flow throughsample is collected by centrifugation at 1000 g for 5 minutes at 4° C.using a DENLEY™ centrifuge. The 1 ml GST resin containing bound materialis transferred to a 15 ml FALCON™ centrifuge tube for subsequent washingand elution steps. Firstly a series of 3 cycles of washings (mixing bygentle inversion) is performed with 15 ml ice cold wash Buffer A (50 mMTris-HCl pH 7.5, 1% Triton X-100, 2 mM DTT) interspersed withcentrifugation at 1000 g for 5 minutes at 4° C. A final single wash stepis performed with 15 ml ice cold wash Buffer B (50 mM Tris-HCl pH 7.5, 2mM DTT) and then centrifuged at 1000 g for 5 minutes at 4° C. The washedGST resin is finally eluted with 4 cycles of 1 ml ice cold elutionbuffer (50 mM Tris-HCl pH 7.5, 10 mM reduced glutathione, 2 mM DTT, 150mM NaCl, 1 mM NaF, 50% ethylene glycol and protease inhibitors)interspersed with centrifugation at 1000 g for 5 minutes at 4° C.Samples are aliquoted and stored at −20° C.

An in vitro kinase assay was established that measures the transfer ofthe terminal phosphate of adenosine triphosphate tophosphatidylinositol. The kinase reaction is performed in a white 96well microtitre plate as a Scintillation Proximity Assay. Each wellcontains 10 μl test compound in 5% dimethylsulphoxide and 20 μl assaymix (40 mM Tris, 200 mM NaCl, 2 mM ethyleneglycol-aminoethyl-tetraaceticacid (EGTA), 15 μg/ml phosphatidylinositol, 12.5 μM adenosinetriphosphate (ATP), 25 mM MgCl₂, 0.1 μCi [³³P]ATP). The reaction isstarted by the addition of 20 μl of enzyme mix (40 mM Tris, 200 mM NaCl,2 mM EGTA containing recombinant GST-p110γ). The plate is incubated atroom temperature for 60 minutes and the reaction terminated by theadding 150 μl of WGA-bead stop solution (40 mM Tris, 200 mM NaCl, 2 mMEGTA, 1.3 mM ethylene diamine tetraacetic acid (EDTA), 2.6 μM ATP and0.5 mg of Wheat Germ Agglutinin-SPA beads (Amersham Biosciences) to eachwell. The plate is sealed, incubated at room temperature for 60 minutes,centrifuged at 1200 rpm and then counted for 1 minute using ascintillation counter. Total activity is determined by adding 10 μl of5% dimethylsulphoxide (DMSO) and non-specific activity is determined byadding 10 μl 50 mM EDTA in place of the test compound.

Compounds of the Examples hereinbelow have IC₅₀ values below 0.6 μM inthe aforementioned assay. For example the compounds of Examples 8, 48,80, 138, 156, 165 and 178 have IC₅₀ values of 0.009, 0.018, 0.013,0.005, 0.002, 0.019 and 0.040 respectively.

Having regard to their inhibition of phosphatidylinositol 3-kinaseenzymes, compounds of formula I in free or pharmaceutically acceptablesalt form, hereinafter alternately referred to as “agents of theinvention”, are useful in the treatment of conditions which are mediatedby the activation of the Pi3 kinase enzymes, particularly inflammatoryor allergic conditions. Treatment in accordance with the invention maybe symptomatic or prophylactic.

Accordingly, agents of the invention are useful in the treatment ofinflammatory or obstructive airways diseases, resulting, for example, inreduction of tissue damage, airways inflammation, bronchialhyperreactivity, remodelling or disease progression. Inflammatory orobstructive airways diseases to which the present invention isapplicable include asthma of whatever type or genesis including bothintrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mildasthma, moderate asthma, severe asthma, bronchitic asthma,exercise-induced asthma, occupational asthma and asthma inducedfollowing bacterial infection. Treatment of asthma is also to beunderstood as embracing treatment of subjects, e.g. of less than 4 or 5years of age, exhibiting wheezing symptoms and diagnosed or diagnosableas “wheezy infants”, an established patient category of major medicalconcern and now often identified as incipient or early-phase asthmatics.(For convenience this particular asthmatic condition is referred to as“wheezy-infant syndrome”.)

Prophylactic efficacy in the treatment of asthma will be evidenced byreduced frequency or severity of symptomatic attack, e.g. of acuteasthmatic or bronchoconstrictor attack, improvement in lung function orimproved airways hyperreactivity. It may further be evidenced by reducedrequirement for other, symptomatic therapy, i.e. therapy for or intendedto restrict or abort symptomatic attack when it occurs, for exampleanti-inflammatory (e.g. corticosteroid) or bronchodilatory. Prophylacticbenefit in asthma may in particular be apparent in subjects prone to“morning dipping”. “Morning dipping” is a recognised asthmatic syndrome,common to a substantial percentage of asthmatics and characterised byasthma attack, e.g. between the hours of about 4 to 6 am, i.e. at a timenormally substantially distant form any previously administeredsymptomatic asthma therapy.

Other inflammatory or obstructive airways diseases and conditions towhich the present invention is applicable include acute lung injury(ALI), adult respiratory distress syndrome (ARDS), chronic obstructivepulmonary, airways or lung disease (COPD, COAD or COLD), includingchronic bronchitis or dyspnea associated therewith, emphysema, as wellas exacerbation of airways hyperreactivity consequent to other drugtherapy, in particular other inhaled drug therapy. The invention is alsoapplicable to the treatment of bronchitis of whatever type or genesisincluding, e.g., acute, arachidic, catarrhal, croupus, chronic orphthinoid bronchitis. Further inflammatory or obstructive airwaysdiseases to which the present invention is applicable includepneumoconiosis (an inflammatory, commonly occupational, disease of thelungs, frequently accompanied by airways obstruction, whether chronic oracute, and occasioned by repeated inhalation of dusts) of whatever typeor genesis, including, for example, aluminosis, anthracosis, asbestosis,chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.

Having regard to their anti-inflammatory activity, in particular inrelation to inhibition of eosinophil activation, agents of the inventionare also useful in the treatment of eosinophil related disorders, e.g.eosinophilia, in particular eosinophil related disorders of the airways(e.g. involving morbid eosinophilic infiltration of pulmonary tissues)including hypereosinophilia as it effects the airways and/or lungs aswell as, for example, eosinophil-related disorders of the airwaysconsequential or concomitant to Löffler's syndrome, eosinophilicpneumonia, parasitic (in particular metazoan) infestation (includingtropical eosinophilia), bronchopulmonary aspergillosis, polyarteritisnodosa (including Churg-Strauss syndrome), eosinophilic granuloma andeosinophil-related disorders affecting the airways occasioned bydrug-reaction.

Agents of the invention are also useful in the treatment of inflammatoryor allergic conditions of the skin, for example psoriasis, contactdermatitis, atopic dermatitis, alopecia areata, erythema multiforma,dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivityangiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus,epidermolysis bullosa acquisita, and other inflammatory or allergicconditions of the skin.

Agents of the invention may also be used for the treatment of otherdiseases or conditions, in particular diseases or conditions having aninflammatory component, for example, treatment of diseases andconditions of the eye such as conjunctivitis, keratoconjunctivitissicca, and vernal conjunctivitis, diseases affecting the nose includingallergic rhinitis, and inflammatory disease in which autoimmunereactions are implicated or having an autoimmune component or aetiology,including autoimmune haematological disorders (e.g. haemolytic anaemia,aplastic anaemia, pure red cell anaemia and idiopathicthrombocytopenia), systemic lupus erythematosus, polychondritis,sclerodoma, Wegener granulamatosis, dermatomyositis, chronic activehepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue,autoimmune inflammatory bowel disease (e.g. ulcerative colitis andCrohn's disease), endocrine opthalmopathy, Grave's disease, sarcoidosis,alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis,primary billiary cirrhosis, uveitis (anterior and posterior),keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitiallung fibrosis, psoriatic arthritis and glomerulonephritis (with andwithout nephrotic syndrome, e.g. including idiopathic nephrotic syndromeor minal change nephropathy). Other diseases or conditions which may betreated with agents of the invention include septic shock, rheumatoidarthritis, osteoarthritis, proliferative diseases such as cancer,athersclerosis, allograft rejection following transplantation, stroke,obesity, restenosis, diabetes, e.g. diabetes mellitus type I (juvenilediabetes) and diabetes mellitus type II, diarrheal diseases,ischemia/reperfusion injuries, retinopathy, such as diabetic retinopathyor hyperbaric oxygen-induced retinopathy, and conditions characterisedby elevated intraocular pressure or secretion of ocular aqueous humor,such as glaucoma.

The effectiveness of an agent of the invention in inhibitinginflammatory conditions, for example in inflammatory airways diseases,may be demonstrated in an animal model, e.g. a mouse or rat model, ofairways inflammation or other inflammatory conditions, for example asdescribed by Szarka et al, J. Immunol. Methods (1997) 202:49-57; Renziet al, Am. Rev. Respir. Dis. (1993) 148:932-939; Tsuyuki et al., J.Clin. Invest. (1995) 96:2924-2931; and Cernadas et al (1999) Am. J.Respir. Cell Mol. Biol. 20:1-8.

The agents of the invention are also useful as co-therapeutic agents foruse in combination with other drug substances such as anti-inflammatory,bronchodilatory or antihistamine drug substances, particularly in thetreatment of obstructive or inflammatory airways diseases such as thosementioned hereinbefore, for example as potentiators of therapeuticactivity of such drugs or as a means of reducing required dosaging orpotential side effects of such drugs. An agent of the invention may bemixed with the other drug substance in a fixed pharmaceuticalcomposition or it may be administered separately, before, simultaneouslywith or after the other drug substance. Accordingly the inventionincludes a combination of an agent of the invention as hereinbeforedescribed with an anti-inflammatory, bronchodilatory or antihistaminedrug substance, said agent of the invention and said drug substancebeing in the same or different pharmaceutical composition. Suchanti-inflammatory drugs include steroids, in particularglucocorticosteroids such as budesonide, beclamethasone, fluticasone,ciclesonide or mometasone, LTB4 antagonists such as those described inU.S. Pat. No. 5,451,700, LTD4 antagonists such as montelukast andzafirlukast, dopamine receptor agonists such as cabergoline,bromocriptine, ropinirole and4-hydroxy-7-[2-[[2-[[3-(2-phenylethoxy)propyl]-sulfonyl]ethyl]-amino]ethyl]-2(3H)-benzothiazoloneand pharmaceutically acceptable salts thereof (the hydrochloride beingViozan®—AstraZeneca), and PDE4 inhibitors such as Ariflo® (GlaxoSmithKline), Roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer),SCH-351591 (Schering-Plough), Arofylline (Almirall Prodesfarma) andPD189659 (Parke-Davis). Such bronchodilatory drugs includeanticholinergic or antimuscarinic agents, in particular ipratropiumbromide, oxitropium bromide and tiotropium bromide, and beta-2adrenoceptor agonists such as salbutamol, terbutaline, salmeterol and,especially, formoterol and pharmaceutically acceptable salts thereof,and compounds (in free or salt or solvate form) of formula I of PCTInternational patent publication No. WO 00/75114, which document isincorporated herein by reference, preferably compounds of the Examplesthereof, especially a compound of formula

and pharmaceutically acceptable salts thereof. Co-therapeuticantihistamine drug substances include cetirizine hydrochloride,acetaminophen, clemastine fumarate, promethazine, loratidine,desloratidine, diphenhydramine and fexofenadine hydrochloride.Combinations of agents of the invention and steroids, beta-2 agonists,PDE4 inhibitors or LTD4 antagonists may be used, for example, in thetreatment of COPD or, particularly, asthma. Combinations of agents ofthe invention and anticholinergic or antimuscarinic agents, PDE4inhibitors, dopamine receptor agonists or LTB4 antagonists may be used,for example, in the treatment of asthma or, particularly, COPD.

Other useful combinations of agents of the invention withanti-inflammatory drugs are those with antagonists of chemokinereceptors, e.g. CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8,CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5antagonists such as Schering-Plough antagonists SC-351125, SCH-55700 andSCH-D, Takeda antagonists such asN-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzocyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminiumchloride (TAK-770), and CCR-5 antagonists described in U.S. Pat. No.6,166,037 (particularly claims 18 and 19), WO 00/66558 (particularlyclaim 8), and WO 00/66559 (particularly claim 9).

The agents of the invention may be administered by any appropriateroute, e.g. orally, for example in the form of a tablet or capsule;parenterally, for example intravenously; by inhalation, for example inthe treatment of inflammatory or obstructive airways disease;intranasally, for example in the treatment of allergic rhinitis;topically to the skin, for example in the treatment of atopicdermatitis; or rectally, for example in the treatment of inflammatorybowel disease.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula I in free form or in the form of apharmaceutically acceptable salt, optionally together with apharmaceutically acceptable diluent or carrier therefor. The compositionmay contain a co-therapeutic agent such as an anti-inflammatory,bronchodilatory or antihistamine drug as hereinbefore described. Suchcompositions may be prepared using conventional diluents or excipientsand techniques known in the galenic art. Thus oral dosage forms mayinclude tablets and capsules. Formulations for topical administrationmay take the form of creams, ointments, gels or transdermal deliverysystems, e.g. patches. Compositions for inhalation may comprise aerosolor other atomizable formulations or dry powder formulations.

When the composition comprises an aerosol formulation, it preferablycontains, for example, a hydro-fluoro-alkane (HFA) propellant such asHFA134a or HFA227 or a mixture of these, and may contain one or moreco-solvents known in the art such as ethanol (up to 20% by weight),and/or one or more surfactants such as oleic acid or sorbitan trioleate,and/or one or more bulking agents such as lactose. When the compositioncomprises a dry powder formulation, it preferably contains, for example,the compound of formula I having a particle diameter up to 10 microns,optionally together with a diluent or carrier, such as lactose, of thedesired particle size distribution and a compound that helps to protectagainst product performance deterioration due to moisture. When thecomposition comprises a nebulised formulation, it preferably contains,for example, the compound of formula I either dissolved, or suspended,in a vehicle containing water, a co-solvent such as ethanol or propyleneglycol and a stabiliser, which may be a surfactant.

The invention includes (A) an agent of the invention in inhalable form,e.g. in an aerosol or other atomisable composition or in inhalableparticulate, e.g. micronised form, (B) an inhalable medicamentcomprising an agent of the invention in inhalable form; (C) apharmaceutical product comprising such an agent of the invention ininhalable form in association with an inhalation device; and (D) aninhalation device containing an agent of the invention in inhalableform.

Dosages of agents of the invention employed in practising the presentinvention will of course vary depending, for example, on the particularcondition to be treated, the effect desired and the mode ofadministration. In general, suitable daily dosages for oraladministration are of the order of 0.1 to 10 mg/kg.

EXAMPLES

Compounds of formula I which are also of formula XIX

are shown in the Table 1 below, the method of preparation beingdescribed thereafter. The table also shows mass spectrometry (MH⁺) data.The examples are in free form.

TABLE 1 Compounds of the invention Ex. R^(a) R^(b) R^(c) R¹ m/s MH+ 1NHSO₂CH₃ H H

326.1 2 NHSO₂C₄H₉ H H

368.1 3

H H

312.1 4 NH₂ Cl H

282.0 5

Cl H

345.9 6

Cl Cl

380.0 7

Br H

390.1 8

Br Br

467.8 9

Br Br

466.7 (M − H⁺) 10

H H

326.1 11

H H

340.1 12

H H

340.0 13

H H

352.1 14

H H

356.1 15

H H

365   16

H H

370   17

H H

311   18 COCH₃ H H

275.1 19 CF₃ H H

301   20 OH H H

249.1 21 OCH₃ OCH₃ H

293.1 22 H CN H

258   23 H CF₃ H

301   24

H H

441.4 25

H H

427.3 26

Cl Cl H 337.8 27

Cl Cl

408.9 28 OCH₃

H

370.9 29 OCH₃

H

414.9 30 OCH₃

H

341.9 31 OCH₃

H

413.0 32 OCH₃

H

400.0 33 OCH₃

H

425.0 34 OCH₃

H

427.0 35 OCH₃

H

427.0 36 OCH₃

H

469.0 37 OCH₃

H

482.1 38 OCH₃

H

439.0 39 OCH₃

H

414.0 40 OCH₃

H

386.0 41 OCH₃

H

341.0 42 OCH₃

H

371.0 43 OCH₃

H

385.1 44 OCH₃

H

366.0 45 H

H

 310.97 46 H

H

 335.97 47 F

H

 328.97 48 Cl

H

 344.94 49 H

H

312.0 50 H

H

395.0 51 H

H

397.0 52 H

H

439.0 53 H

H

384.0 54 H

H

356.0 55 H

H

426.1 56 F

H

 329.97 57 Cl

H

346.0 58

H H H 268.9 59

H H

340.0 60

H H

398.0 61

H H

370.0 62

H H

384.0 63

Br H

388.8 64

F H

329.02 65

CF₃ H

378.5 66

Cl H

344.7 67

H

 409.14 68

H

 411.11 69

H

 411.14 70

H

 425.02 71

H

 439.15 72

F H H  286.99 73

F H

 358.04 74

H H

277.0 75

H H

320.1 76

H H

329.1

Preparation of Specific Examples

Abbreviations used are as follows: DCM is dichloromethane, DIPEA isdiisopropylethylamine DME is dimethoxyethane, HATU isO-(7-azabenzotriazol-1-yl)-N,N,-N′,N′-tetramethyl-uroniumhexafluorophophate, NBS is N-bromosuccinimide and THF istetrahydrofuran.

Example 1N-[5-(4-Methanesulfonylamino-phenyl)-4-methyl-thiazol-2-yl]-acetamide 1aN[5-(4-Amino-phenyl)-4-methyl-thiazol-2-yl]-acetamide

N-[4-Methyl-5-(4-nitro-phenyl)-thiazol-2-yl]-acetamide (J. Liebscher, E.Mitzner, Synthesis, 1985, (4), p 414) (10.0 g, 3.6 mmol) is dissolved inethyl acetate/THF (5/1, 600 ml) and stirred at room temperature under anatmosphere of argon. The solution is then treated with 10% palladium oncarbon (10 g). The reaction mixture is purged three times with nitrogenand placed under an atmosphere of hydrogen overnight. The mixture isthen filtered through Celite™ filter material and the catalyst is washedwith tetrahydrofuran (600 ml). The solvent is removed in vacuo to leaveN-[5-(4-amino-phenyl)-4-methyl-thiazol-2-yl]-acetamide as an off-whitesolid.

1b)N-[5-(4-Methanesulfonylamino-phenyl)-4-methyl-thiazol-2-yl]-acetamide

N-[5-(4-Amino-phenyl)-4-methyl-thiazol-2-yl]-acetamide (0.05 g, 0.20mmol) is dissolved in dimethylformamide (1 ml) and treated by a solutionof methylsulfonyl chloride (0.0232 g, 0.20 mmol) in drydimethylformamide (1 ml) followed by 2M aqueous sodium carbonatesolution (0.20 ml, 0.40 mmol). The reaction mixture is stirred at roomtemperature for 18 hours. The solvent is removed in vacuo and theresidue is purified by chromatography to give the title compound. MH⁺(ESMS): 326.1

Example 2N-[5-[4-(Butane-1-sulfonlamino)-phenyl]-4-methyl-thiazol-2-yl]-acetamide

This is prepared as described in example 1b by replacing methylsulfonylchloride with n-butylsulfonyl chloride. MH⁺ (ESMS): 368.1

Example 3 N-[4-Methyl-5-(4-sulfamoyl-phenyl)-thiazol-2-yl]-acetamide 3a)4-(2-Acetylamino-4-methyl-thiazol-5-yl)-benzenesulfonyl chloride

N-[5-(4-Amino-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 1a) (7.9g, 31.9 mmol) in suspension in glacial acetic acid (250 ml) is treatedwith a 32% aqueous HCl solution (40 ml). The resulting solution is thencooled approximately to 10° C. and treated dropwise with a solution ofsodium nitrite (2.2 g, 31.9 mmol) in water (2 ml). After 10 minutes thereaction mixture is added to a stirred solution of SO₂/AcOH/CuCl₂/H₂O(200 ml) (the preparation of the reagent is described below). Thereaction mixture is allowed to warm to room temperature and is stirredovernight.

The reaction mixture is then poured into water (1000 ml) and extractedwith ethyl acetate (3×300 ml). The combined organic layers are washedwith water (2×250 ml) followed by brine (200 ml) and dried over MgSO₄.After filtration the solvent is removed in vacuo to give4-(2-acetylamino-4-methyl-thiazol-5-yl)-benzenesulfonyl chloride. MH⁺(TOF, MS ES₊): 248.1

Preparation of the Reagent SO₂/AcOH/CuCl₂/H₂O

According to the reported procedure (E. E. Gilbert, Synthesis 1969,1-10, p 6), glacial acetic acid (100 ml) vigorously stirred at roomtemperature is treated by bubbling SO₂ gas. Once a saturated solution isachieved (approximately 10 g per 100 ml), the solution is treated withcopper (II) chloride (4 g) in water (5 ml). The resulting mixture isallowed to settle to give a green solution.

3b) N-[4-Methyl-5-(4-sulfamoyl-phenyl)-thiazol-2-yl]-acetamide

4-(2-Acetylamino-4-methyl-thiazol-5-yl)-benzenesulfonyl chloride (3a)(3.8 g, 11.5 mmol) is dissolved in dioxane (50 ml) with stirring. Sodiumcarbonate (2.45 g, 23 mmol) is added followed by a solution of ammoniain dioxane (50 ml, 0.75 M). After stirring for 2 hours at roomtemperature diethyl ether (120 ml) is added and the solid precipitate isremoved by filtration. The solid is stirred in tetrahydrofuran (200 ml)and the mixture is then filtered through Celite™ filter material toremove inorganic material. Removal of the solvent affordsN-[4-methyl-5-(4-sulfamoyl-phenyl)-thiazol-2-yl]-acetamide.

Example 4N-[5-(4-Amino-3-chloro-phenyl)-4-methyl-thiazol-2-yl]-acetamide

Following a general procedure for chlorination of anilines (S.Mukhopadhyay, K. H. Chandnani, S. B. Chandalia, Organic Process Research& Development, 1999 3, p 196) hydrogen peroxide (27% solution in water,5.1 ml, 40 mmol) is added dropwise over 30 minutes toN-[5-(4-amino-phenyl)-4-methyl-thiazol-2-yl]-acetamide 1a (5.0 g, 20mmol) stirred in acetic acid (30 ml) and concentrated hydrochloric acid(6.7 ml) at room temperature. When the addition is complete the mixtureis poured onto ice water and the pH adjusted to alkaline by addition of4M aqueous sodium hydroxide solution. The mixture is then extracted withethyl acetate, followed by dichloromethane. The combined organicextracts are dried (MgSO₄) and the product mixture is absorbed onsilica. Chromatography on silica eluting with hexane—ethyl acetate (1:1)affords three fractions: The first fraction is identified asN-[5-(4-amino-3,5-dichloro-phenyl)-4-methyl-thiazol-2-yl]-acetamide(Example 4a). MH⁺ (TOF, MS ES+) 316.1, 318.1, 320.1. The second fractionis identified as the title compound,N-[5-(4-amino-3-chloro-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example4b). MH⁺ (AP⁺): 282, 284 (3:1). The third fraction is unreacted startingmaterial (Example 1a).

Examples 5 to 8

These products are obtained in a two step sequence from thecorresponding anilines (4a, 4b, 7a, 8a) following analogous conditionsto those described for the conversion ofN-[5-(4-amino-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 1a) tothe corresponding sulfonamide (Example 3b).

Example 5N-[5-(3-Chloro-4-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide

Using N-[5-(4-amino-3-chloro-phenyl)-4-methyl-thiazol-2-yl]-acetamide(Example 4b) affords the title compound as an orange solid. MH⁺ (TOF, MSES₊) 345.9, 347.9

Example 6N-[5-(3,5-Dichloro-4-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide

UsingN-[5-(4-amino-3,5-dichloro-phenyl)-4-methyl-thiazol-2-yl]-acetamide(Example 4a) affords the product as a white crystalline solid. MH⁺ (TOF,MS ES₊) 380.0, 382.0, 384.0

Example 7N-[5-(3-Bromo-4-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide 7a)N-[5-(4-Amino-3-bromo-phenyl)-4-methyl-thiazol-2-yl]-acetamide

NBS (2.52 g, 14.7 mmol) is added to a stirred solution ofN-[5-(4-amino-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 1a) (3.5g, 14.7 mmol) in dry dimethylsulphoxide (50 ml) at 10° C. After 10minutes the solution is diluted with water (200 ml) and the resultingprecipitate is removed by filtration. Crystallisation from ethylacetate—methanol affords the title compound. MH⁺ (TOF, MS ES₊): 325.9,328.9

7b) N-[5-(3-Bromo-4-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide

The title compound is obtained fromN-[5-(4-amino-3-bromo-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example7a) to give a cream solid. MH⁺ (TOF, MS ES₊) 390.1, 391.1,

Example 8N-[5-(3,5-Dibromo-4-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide8a) N-[5-(4-Amino-3,5-dibromo-phenyl)-4-methyl-thiazol-2-yl]-acetamide

Bromine (0.083 ml, 1.6 mmol) is added dropwise over 10 minutes to astirred solution ofN-[5-(4-amino-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 1a)(0.20 g, 0.81 mmol) in 1,4-dioxane (5 ml). When the addition is completethe mixture is diluted with saturated sodium hydrogen carbonate solution(30 ml) and extracted with dichloromethane (2×30 ml). The combinedorganic extracts are dried (MgSO₄), filtered, and the solvent removed togive a dark solid. Crystallisation from methanol—dichloromethane yieldsthe tide compound. MH⁺ (TOF, MS ES₊): 403.7, 405.6, 407.6

8b)N-[5-(3,5-Dibromo-4-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide

Using N-[5-(4-amino-3,5-dibromo-phenyl)-4-methyl-thiazol-2-yl]-acetamide(8a) affords the title compound. MH⁺ (TOF, MS ES₊): 467.8, 469.8, 471.8

Example 94-(2-Acetylamino-4-methyl-thiazol-5-yl)-2,6-dibromo-benzenesulfonic acid

This compound is obtained as a minor component in the preparation ofexample 5 fromN-[5-(4-amino-3-bromo-phenyl)-4-methyl-thiazol-2-yl]-acetamide; Thecrude product mixture obtained in the preparation of example 8 isfiltered through Celite™ filter material washing with tetrahydrofuran togiveN-[5-(3,5-dibromo-4-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide(8). Washing the Celite™ filter material with ethanol then affords thetitle compound. M-H+(AP⁻) 466.7, 468.6, 470.6

Example 10N-[4-Methyl-5-(4-methylsulfamoyl-phenyl)-thiazol-2-yl]-acetamide

4-(2-Acetylamino-4-methyl-thiazol-5-yl)-benzenesulfonyl chloride(Example 3a) (0.05 g, 0.15 mmol) is dissolved in dioxane (1 ml). Thesolution is treated with 2M aqueous sodium carbonate (0.15 ml, 0.24mmol) followed by the addition of a 33% solution of methylamine inethanol (0.08 ml, 0.6 mmol). The reaction mixture is stirred overnight.The solvent is removed in vacuo and the residue is purified by prepLC-MS i.e. liquid chromatography mass spectrometry to giveN-[4-Methyl-5-(4-methylsulfamoyl-phenyl)-thiazol-2-yl]-acetamide. MH⁺(ESMS): 326.1

Examples 11 to 16

These compounds, namelyN-[5-(4-dimethylsulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Mp279-281° C.),N-[5-(4-ethylsulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide,N-[5-(4-cyclopropylsulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide,N-{5-[4-(2-hydroxy-ethylsulfamoyl)-phenyl]-4-methyl-thiazol-2-yl}-acetamide,N-{5-[4-(2-cyano-ethylsulfamoyl)-phenyl]-4-methyl-thiazol-2-yl}-acetamideandN-{5-[4-(2-methoxy-ethylsulfamoyl)-phenyl]-4-methyl-thiazol-2-yl}-acetamiderespectively, are prepared in an analogous manner to Example 10 byreaction of the appropriate amine with4-(2-acetylamino-4-methyl-thiazol-5-yl)-benzenesulfonyl chloride (3a).

Example 17N-[5-(4-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide 17a)N-(4-Methyl-thiazol-2-yl)-acetamide

2-Amino-4-methylthiazole (10.0 g, 87.6 mmol) is dissolved in drypyridine (75 ml) at room temperature. This solution is then treateddropwise with acetyl chloride (6.3 ml, 87.6 mmol). After 2 hours, thereaction mixture is poured into water (1000 ml), and extracted withethyl acetate (3×250 ml). The combined organic layers are washed withwater (2×200 ml), brine (200 ml), dried over MgSO₄, filtered andconcentrated in vacuo. The residue is dissolved in toluene (200 ml)followed by the removal of the solvent in vacuo. The solid thus obtainedis dried in vacuo to give the title compound.

17b) N-(5-Bromo-4-methyl-thiazol-2-yl)-acetamide

N-(4-Methyl-thiazol-2-yl)-acetamide (Example 17a) (4.0 g, 25.6 mmol) isdissolved in glacial acetic acid (100 ml) at room temperature. Thissolution is then treated portionwise with N-bromosuccinimide (4.6 g,25.6 mmol). After 48 hours the reaction mixture is poured into water(1000 ml) and extracted with ethyl acetate (3×250 ml). The combinedorganic layers are washed with water (200 ml), brine (200 ml), driedover MgSO₄, filtered and concentrated in vacuo. The residue is dissolvedin toluene (100 ml) followed by the removal of the solvent in vacuo.This is repeated twice more and the resulting solid is dried in vacuo at40° C. to give N-(5-bromo-4-methyl-thiazol-2-yl)-acetamide.

17c) N-[5-(4-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide

N-(5-Bromo-4-methyl-thiazol-2-yl)-acetamide (Example 17b) (0.1 g, 0.43mmol) is dissolved in DME (2 ml) at room temperature. This solution istreated with [(4-methylsulfonyl) phenyl] boronic acid (0.172 g, 0.86mmol), followed by 2M aqueous Na₂CO₃ (0.63 ml, 1.29 mmol) andbis(triphenylphosphine)palladium(II)chloride (0.03 g, 0.043 mmol). Themixture is then heated at 80° C. for 4 hours. The solvent is removed invacuo and the residue is purified by preparative LCMS to giveN-[5-(4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide. MH⁺(ESMS): 311.0, Mp 251-253° C.

Examples 18 to 23

These compounds, namelyN-[5-(4-acetyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide,N-[4-methyl-5-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-acetamide,N-[5-(4-hydroxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide,N-[5-(3,4-dimethoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide,N-[5-(3-cyano-phenyl)-4-methyl-thiazol-2-yl]-acetamide andN-[4-methyl-5-(3-trifluoromethyl-phenyl)-thiazol-2-yl]-acetamiderespectively, are prepared in an analogous manner from the appropriateboronic acid following the procedure described for Example 17.

Example 24{3-[5-(4-Dimethylsulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-aceticacid: ethyl ester 24a)4-(2-Amino-4-methyl-thiazol-5-yl)-N,N-dimethyl-benzenesulfonamide

Concentrated hydrochloric acid (15 ml) is added to a stirred suspensionof N-[5-(4-dimethylsulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide(example 11) (6.26 g, 18.5 mmol) in ethanol (120 ml). The reaction isheated at 85° C. until no starting material remains (4 hours). Thereaction is allowed to cool and the solvent removed to give thehydrochloride salt as a yellow solid. Aqueous sodium hydroxide (4M) isadded and the mixture is stirred vigorously for 30 minutes beforeextracting with chloroform followed by ethyl acetate. The combinedorganic extracts are dried (MgSO₄), filtered and the solvent is removedto give the title compound. MH⁺ (TOF, MS, ES₊): 427.3

24b){3-[5-(4-Dimethylsulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-aceticacid ethyl ester

4-(2-Amino-4-methyl-thiazol-5-yl)-N,N-dimethyl-benzenesulfonamide(Example 24a) (0.083 g, 0.28 mmol) and ethyl isocyanatoacetate (0.05 ml,0.34 mmol) are stirred in dimethylformamide at 100° C. for 3 hours. Themixture is then partitioned between 1M aqueous hydrochloric acid andethyl acetate. The organic extract is washed with brine, dried overMgSO₄ and the solvent removed in vacuo. Purification by preparative HPLCaffords the title compound. MH⁺ (TOF, MS, ES₊): 441.4

Example 253-{3-[5-(4-Dimethylsulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-propionicacid ethyl ester

Using 4-(2-amino-4-methyl-thiazol-5-yl)-N,N-dimethyl-benzenesulfonamide(Example 24a) (0.083 g, 0.28 mmol) and replacing ethyl isocyanatoacetatewith ethyl 3-isocyanatopropion-ate (0.05 ml, 0.34 mmol) in the abovereaction affords the title compound.

Example 264-(2-Amino-4-methyl-thiazol-5-yl)-2,6-dichloro-benzenesulfonamide

A solution ofN-[5-(3,5-dichloro-4-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide(Example 6) (0.70 g, 1.84 mmol) in aqueous hydrochloric acid (5M, 10 ml)and ethanol (20 ml) is heated at reflux for 90 minutes. When cool, themixture is concentrated to remove ethanol and the aqueous solution isbrought to pH 9 by addition of aqueous sodium hydroxide (4M). Theproduct is extracted with n-butanol (50 ml) and the organic extract isdried over MgSO₄. Removal of the solvent followed by chromatography onsilica (eluting with ethyl acetate—hexane, 2:1 increasing to 4:1)affords the title compd. MH⁺ (MS, AP⁺): 337.8, 339.5

Example 272,6-Dichloro-4-[2-(3-ethyl-ureido)-4-methyl-thiazol-5-yl]-benzenesulfonamide

Ethyl isocyanate (0.015 ml, 0.19 mmol) is added to a stirred solution of4-(2-amino-4-methyl-thiazol-5-yl)-2,6-dichloro-benzenesulfonamide(Example 26) (0.043 g, 0.127 mmol) in dry dimethylformamide (1.0 ml)under argon. After heating at 85° C. for 3 hours more ethyl isocyanate(0.015 ml, 0.19 mmol) is added and heating continued for a further hour.The reaction is concentrated in vacuo and the product is purified bychromatography on silica eluting with ethyl acetate—hexane (1:1increasing to 4:1) to give the title compound. MH⁺ (TOF, MS, ES⁺):408.9, 410.9, 412.8

Example 285-[2-(3-Ethyl-ureido)-4-methyl-thiazol-5-yl]-2-methoxy-benzenesulfonamide28a) N-[5-(4-Methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide

4-methoxyphenylacetone (10 g, 60.9 mmol), N-acetylthiourea (7.2 g, 60.9mmol) and iodine (15.46 g, 60.9 mmol) in pyridine (50 ml) are stirred at70° C. for 16 hours. The mixture is concentrated and the residue ispurified by chromatography on silica with iso-hexane-ethyl acetate (1:1)to give the titled compound.

28b) 5-(4-Methoxy-phenyl)-4-methyl-thiazol-2-ylamine

A solution of concentrated hydrochloric acid HCl (20 ml) in water (30ml) is added to N-[5-(4-Methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide(Example 28a) (2 g, 7.63 mmol) in ethanol. After 5 hours at reflux, thereaction is poured into water (600 ml) and the pH is adjusted to 9/10with 2.5 M NaOH. The aqueous layer is then extracted with ethyl acetate(3×200 ml). The combined organic layers are dried over MgSO₄, filteredand concentrated to afford5-(4-Methoxy-phenyl)-4-methyl-thiazol-2-ylamine.

28c) 1-Ethyl-3-[5-(4-methoxy-phenyl)-4-methyl-thiazol-2-yl]urea

Ethyl isocyanate (1.2 ml, 14.18 mmol) is added to5-(4-methoxy-phenyl)-4-methyl-thiazol-2-ylamine (Example 28b) (1.56 g,7.09 mmol) in dioxane (100 ml). After 5 hours at 85° C. the reactionmixture is concentrated to yield1-ethyl-3-[5-(4-methoxy-phenyl)-4-methyl-thiazol-2-yl]urea as a brownsolid.

28d)5-[2-(3-Ethyl-ureido)-4-methyl-thiazol-5-yl]-2-methoxy-benzenesulfonylchloride

A suspension of1-ethyl-3-[5-(4-methoxy-phenyl)-4-methyl-thiazol-2-yl]urea (Example 28c)(1.0 g, 3.44 mmol) in dichloromethane (15 ml) is added portionwise tochlorosulfonic acid (25 ml, excess) cooled at −10° C. The temperature iskept below 0° C. throughout the addition. The reaction mixture is leftto warm up to room temperature. After 3 hours, the reaction mixture ispoured carefully onto ice (2 litres). Once ice is melted, the aqueouslayer is extracted with dichloromethane (DCM) (3×200 ml). The combinedorganic layers are washed with brine, dried over MgSO₄, filtered andconcentrated to afford5-[2-(3-ethyl-ureido)-4-methyl-thiazol-5-yl]-2-methoxybenzenesulfonylchloride.

28e)5-[2-(3-Ethyl-ureido)-4-methyl-thiazol-5-yl]-2-methoxy-benzenesulfonamide

To a stirred solution of5-[2-(3-ethyl-ureido)-4-methyl-thiazol-5-yl]-2-methoxybenzenesulfonylchloride (Example 28d) (0.2 g, 0.514 mmol) in dioxane (10ml) is added 2 M Na₂CO₃ (0.515 ml) followed by 0.5 M NH₃ in dioxane(2.06 ml). After 2 hours at room temperature, the reaction mixture ispoured into water (200 ml) then extracted with ethyl acetate (3×50 ml).The combined organic layers are dried over MgSO₄, filtered andconcentrated to afford5-[2-(3-ethyl-ureido)-4-methyl-thiazol-5-yl]-2-methoxy-benzenesulfonamideas a yellow powder.

Example 295-[2-(3-Ethyl-ureido)-4-methyl-thiazol-5-yl]-.N.-(2-hydroxy-ethyl)-2-methoxy-benzenesulfonamide

To 5-[2-(3-Ethyl-ureido)-4-methyl-thiazol-5-yl]-2-methoxybenzenesulfonylchloride (Example 28d) (0.2 g, 0.514 mmol) in dioxane (10ml) is added 2M Na₂CO₃ (0.515 ml) followed by ethanolamine (0.031 ml,0.514 mmol). After 2 hours at room temperature, the reaction mixture ispoured into water (150 ml)/ethylacetate (50 ml) and sonicated. Thelayers are separated then the aqueous layer is extracted with ethylacetate (3×50 ml). The combined organic layers are dried over MgSO4,filtered and concentrated to afford a sticky oil which is dissolved in aminimum amount of DCM/methanol and dried at reduced pressure to afford5-[2-(3-ethyl-ureido)-4-methyl-thiazol-5-yl]-N-(2-hydroxy-ethyl)-2-methoxy-benzenesulfonamideas a yellow foam.

Example 30N-[5-(4-Methoxy-3-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide30a) 2-Methoxy-5-(2-oxo-propyl)-benzenesulfonamide

4-methoxyphenylacetone (5 g, 30 mmol) is added dropwise tochlorosulfonic acid (14.25 ml, 0.21 mol) at below 0° C. and the mixtureis stirred at room temperature for 2 hours. The mixture is poured intocrushed ice and extracted with ethyl acetate. The ethyl acetate layer iswashed with water and dried over Na₂SO₄. After removal of the solvent,the residue is dissolved in tetrahydrofuran (50 ml) and concentratedammonia (8 ml) is added dropwise. The mixture is stirred at roomtemperature overnight and concentrated. To the residue is added water,the precipitates are collected by filtration and recrystallised frommethanol to give the titled compound.

30b) 5-(1-Bromo-2-oxo-propyl)-2-methoxy-benzenesulfonamide

2-Methoxy-5-(2-oxo-propyl)-benzenesulfonamide (Example 30a) (0.5 g, 2.05mmol) in dry THF (15 ml) is added dropwise to a solution of2-carboxyethyltriphenylphosphonium perbromide (1.24 g, 2.15 mmol) in dryTHF (10 ml). The mixture is stirred at room temperature for 3 hours,filtered and then concentrated. The residue is purified bychromatography on silica with hexane-ethyl acetate (1:1) to give thetitled compound.

30c)N-[5-(4-Methoxy-3-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide

5-(1-Bromo-2-oxo-propyl)-2-methoxy-benzenesulfonamide (Example 30b) (0.2g, 0.64 mmol) and N-acetylthiourea (0.075 g, 0.64 mmol) in ethanol (3ml) are stirred at 70° C. for 4 hours. The mixture is concentrated andthe residue is recrystallised from ethanol to give an off-white solid.MH⁺ (ESMS): Mp 341.9° C.

Example 31N-{5-[3-(2-Dimethylamino-ethylsulfamoyl)-4-methoxy-phenyl]-4-methyl-thiazol-2-yl}-acetamide31a) N-[5-(4-Methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide

4-methoxyphenylacetone (10 g, 60.9 mmol), N-acetylthiourea (7.2 g, 60.9mmol), iodine (15.46 g, 60.9 mmol) in pyridine (50 ml) are stirred at70° C. for 16 hours. The mixture is concentrated and the residue ispurified by chromatography on silica with hexane-ethyl acetate (1:1) togive the titled compound.

31b)N-{5-[3-(2-Dimethylamino-ethylsulfamoyl)-4-methoxy-phenyl]-4-methyl-thiazol-2-yl}-acetamide

To N-[5-(4-Methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example28a) (0.0947 g, 0.361 mmol) is added at 0° C. chlorosulfonic acid (3 ml)followed by dichloromethane (1 ml). The reaction mixture is stirredbelow 0° C. for 2 hours then poured into crushed ice and extracted withdichloromethane (3×5 ml). The organic layers are combined and dried overMgSO₄. The solvent is removed to give5-(2-acetylamino-4-methyl-thiazol-5-yl)-2-methoxy-benzenesulfonylchloride, which is dissolved into dioxane (2 ml). To this solution isadded N,N-dimethyl-ethylenediamine (0.0636 g, 0.72 mmol) and 2M Na₂CO₃(0.5 ml). The reaction mixture is stirred at room temperature for 2hours. The mixture is concentrated and the residue is taken into water(2 ml) and extracted with dichloromethane (3×5 ml). The combined organiclayers are dried over MgSO₄. After filtration the solvent is removed invacuo to give the titled compound which is dried overnight in vacuumoven at 25° C. MH⁺ (ESMS): Mp 413.0° C.

Examples 32 to 40

These compounds namelyN-{5-[4-methoxy-3-(2-methoxy-ethylsulfamoyl)-phenyl]-4-methyl-thiazol-2-yl}-acetamide,N-{5-[4-methoxy-3-(4-methyl-piperazine-1-sulfonyl)-phenyl]-4-methyl-thiazol-2-yl}-acetamide,N-{5-[3-(3-dimethylamino-propylsulfamoyl)-4-methoxy-phenyl]-4-methyl-thiazol-2-yl}-acetamide,N-(5-{3-[(2-dimethylamino-ethyl)-methyl-sulfamoyl]-4-methoxy-phenyl}-4-methyl-thiazol-2-yl)-acetamide,N-{5-[4-methoxy-3-(3-morpholin-4-yl-propylsulfamoyl)-phenyl]-4-methyl-thiazol-2-yl}-acetamide,N-{5-(4-methoxy-3-[3-(4-methyl-piperazin-1-yl)-propylsulfamoyl]-phenyl}-4-methyl-thiazol-2-yl)-acetamide,N-{5-[4-methoxy-3-(2-pyrrolidin-1-yl-ethylsulfamoyl)-phenyl]-4-methyl-thiazol-2-yl}-acetamide,N-{5-[4-methoxy-3-(3-methoxy-propylsulfamoyl)-phenyl]-4-methyl-thiazol-2-yl}-acetamideandN-{5-[3-(2-hydroxy-ethylsulfamoyl)-4-methoxy-phenyl]-4-methyl-thiazol-2-yl}-acetamiderespectively, are prepared by replacing N,N-dimethylethylenediamine withthe appropriate amine in the above procedure described for thepreparation ofN-{5-[3-(2-dimethylamino-ethylsulfamoyl)-4-methoxy-phenyl]-4-methyl-thiazol-2-yl}-acetamide(Example 31b) to afford the title compounds.

Example 41N-[5-(3-Methanesulfonyl-4-methoxy-phenyl)-4-methyl-thiazol-2]-acetamide41a) 5-(2-Acetylamino-4-methyl-thiazol-5-yl)-2-methoxy-benzenesulfonylchloride

To chlorosulfonic acid (25 ml, excess), cooled at −10° C., is addedportionwise a suspension ofN-[5-(4-methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 31a)(1.0 g, 3.8 mmol) in DCM (10 ml). The temperature is kept below 0° C.throughout the addition. The reaction mixture is left to warm up to roomtemperature. After 2 hours, the reaction mixture is poured carefullyonto ice (500 ml). Once the ice is melted, the aqueous layer isextracted with DCM (3×200 ml). The combined organic layers are washedwith brine (150 ml), dried over MgSO₄, filtered and concentrated toafford 5-(2-acetylamino-4-methyl-thiazol-5-yl)-2-methoxybenzene-sulfonylchloride.

41b)N-[5-(3-Methanesulfonyl-4-methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide

To a stirred solution of sodium sulfite (1.05 g, 8.31 mmol) and sodiumhydrogen carbonate (0.71 g, 8.31 mmol) in water (10 ml) at 70° C. isadded a solution of5-(2-acetylamino-4-methyl-thiazol-5-yl)-2-methoxy-benzenesulfonylchloride (Example 41a) (1.5 g, 4.16 mmol) in 1,4-dioxane (20 ml). After30 minutes, the reaction mixture is concentrated to yield the sodiumsulfinate intermediate as an off-white solid. To the sulfinateintermediate (0.5 g, 1.43 mmol) in DMF (10 ml) is added iodomethane(0.09 ml, 1.43 mmol). After 2 hours at 40° C., the reaction mixture ispoured into water (250 ml) and extracted with ethyl acetate (3×50 ml).The combined organic layers are dried over MgSO₄, filtered andconcentrated to affordN-[5-(3-methanesulfonyl-4-methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide.

Examples 42 to 44

These compounds, namelyN-{5-[3-(2-hydroxy-ethanesulfonyl)-4-methoxy-phenyl]-4-methyl-thiazol-2-yl}-acetamide,N-{5-[3-(3-hydroxy-propane-1-sulfonyl)-4-methoxy-phenyl]-4-methyl-thiazol-2-yl}-acetamide,andN-[5-(3-Cyanomethanesulfonyl-4-methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamiderespectively, are synthesised following the same procedure as 41,replacing methyl iodide in the above procedure with the appropriatealkyl iodide

Example 45N-[5-(3-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide

N-[4-Methyl-5-(3-nitro-phenyl)-thiazol-2-yl]-acetamide (Example 49b) isconverted into the aniline using the procedure described in Example 1aand this material is converted into the title compound following theprocedure described in Example 41b.

Example 46N-[5-(3-Cyanomethanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide

N-[4-Methyl-5-(3-nitro-phenyl)-thiazol-2-yl]-acetamide (49b) isconverted into the aniline using the procedure described in Example 1aand this material is converted into the title compound following theprocedure described in Example 41b, replacing methyl iodide in thisprocedure with iodoacetonitrile.

Example 47N-[5-(4-Fluoro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide47a) 2-Fluoro-5-(2-oxo-propyl)-benzenesulfonyl chloride

To chlorosulfonic acid (25 ml, excess) cooled at −10° C. is addeddropwise 4-fluorophenyl acetone (1.0 g, 6.57 mmol). The temperature iskept below 0° C. throughout the addition. The reaction mixture is thenleft to warm up to room temperature overnight. The reaction mixture ispoured carefully onto ice (1500 ml). Once ice is melted, the aqueouslayer is extracted with DCM (3×250 ml). The combined organic layers aredried over MgSO₄, filtered and concentrated to afford the titledcompound as an off-white solid.

47b) 1-(4-Fluoro-3-methanesulfonyl-phenyl)-propan-2-one

To a stirred solution of sodium sulfite (0.5 g, 3.99 mmol) and sodiumhydrogen carbonate (0.34 g, 3.99 mmol) in water (10 ml) at 70° C. isadded a solution of 2-fluoro-5-(2-oxo-propyl)-benzenesulfonyl chloride(Example 47a) (0.5 g, 1.99 mmol) in 1,4-dioxane (20 ml). After 1 hour,the reaction mixture is concentrated to yield the sulfinateintermediate. To the sulfinate intermediate (0.47 g, 1.97 mmol) in DMF(20 ml) is added iodomethane (0.12 ml, 1.97 mmol). After 1 hour at 40°C., the reaction mixture is poured into water (400 ml) and extractedwith ethyl acetate (3×100 ml). The combined organic layers are driedover MgSO₄, filtered and concentrated. The residue is left overnight inthe vacuum oven to afford the titled compound as a viscous oil.

47c) 1-Bromo-1-(4-Fluoro-3-methanesulfonyl-phenyl)-propan-2-one

To 1-(4-fluoro-3-methanesulfonyl-phenyl)-propan-2-one (Example 47b)(0.23 g, 1 mmol) in dry THF (5 ml) is added under inert atmosphere anddropwise a solution of 2-carboxethyltriphenylphosphonium tribromide (0.6g, 1.05 mmol). After 2.5 hours at room temperature the reaction mixtureis filtered then concentrated to give a viscous orange oil which ispurified by chromatography eluting with isohexane-ethyl acetate (4:1then 2:1) to give the titled compound.

47d)N-[5-(4-Fluoro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide

A mixture of 1-bromo-1-(4-fluoro-3-methanesulfonyl-phenyl)-propan-2-one(Example 47c) (0.17 g, 0.55 mmol) and N-acetylthiourea (0.065 g, 0.55mmol) in ethanol is heated at 70° C. for 3 hours then at roomtemperature over two days. The reaction mixture is poured into water(200 ml) and extracted with ethyl acetate (3×50 ml). The combinedorganic layers are dried over MgSO₄, filtered and concentrated to afforda viscous solid. This solid in a minimum amount of ethyl acetate issonicated to give a suspension which is then heated until all solid hasdissolved then left to cool to room temperature overnight. The whitecrystalline solid is filtered off to afford the titled compound.

Example 48N-[5-(4-Chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide

The title compound is prepared following the same route asN-[5-(4-Fluoro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide(Example 47) by replacing 4-fluorophenyl acetone with 4-chlorophenylacetone.

Example 49 N-[4-Methyl-5-(3-sulfamoyl-phenyl)-thiazol-2-yl]-acetamide49a) 1-Bromo-1-(3-nitro-phenyl)-propan-2-one

A stirred solution of 3-nitrophenylacetone (0.5 g, 13.9 mmol) in THF (10ml) at room temperature is treated with polymer supported pyridinehydrobromide perbromide (1.4 g, 2 mmol Br₃ ⁻/g). The reaction mixture isstirred overnight, then filtered and concentrated in vacuo. The residueis purified by chromatography on silica with iso-hexane-ethyl acetate(6:1) to give the titled compound.

49b) N-[4-Methyl-5-(3-nitro-phenyl)-thiazol-2-yl]-acetamide

A mixture of 1-bromo-1-(3-nitro-phenyl)-propan-2-one (Example 49a) (0.5g, 1.94 mmol) and N-acetylthiourea (0.23 g, 1.94 mmol) in ethanol (10ml) is stirred at 70° C. for 2 hours. After cooling the reaction to roomtemperature, the precipitated product is removed by filtration and driedunder vacuum to give the titled compound (0.28 g).

49c) N-[4-Methyl-5-(3-sulfamoyl-phenyl)-thiazol-2-yl]-acetamide

N-[4-Methyl-5-(3-nitro-phenyl)-thiazol-2-yl]-acetamide (Example 49b) isconverted into the aniline using the procedure described in Example 1aand this material is converted into the corresponding sulfonamidefollowing the procedure described in Example 3.

Examples 50 to 54

These compounds, namelyN-{4-methyl-5-[3-(4-methyl-piperazine-1-sulfonyl)-phenyl]-thiazol-2-yl}-acetamide,N-{5-[3-(3-dimethylamino-propylsulfamoyl)-phenyl]-4-methyl-thiazol-2-yl}-acetamide,N-{4-methyl-5-[3-(3-morpholin-4-yl-propylsulfamoyl)-phenyl]-thiazol-2-yl}-acetamide,N-{5-[3-(3-methoxy-propylsulfamoyl)-phenyl]-4-methyl-thiazol-2-yl}-acetamideandN-{5-[3-(2-hydroxy-ethylsulfamoyl)-phenyl]-4-methyl-thiazol-2-yl}-acetamiderespectively, are prepared as described for Example 49 by replacingammonia in the final reaction with the appropriate amine.

Example 55N-(3-Dimethylamino-propyl)-3-[2-(3-ethyl-ureido)-4-methyl-thiazol-5-yl]benzenesulfonamide

The title compound was prepared from Example 51 using hydrolysisconditions described in example 26 followed by reaction with ethylisocyanate as described in Example 27.

Example 56N-[5-(4-Fluoro-3-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide

The title compound is prepared from 4-fluorophenyl acetone via2-fluoro-5-(2-oxo-propyl)-benzenesulfonyl chloride (Example 47a)following an identical sequence of reactions used for the synthesis ofN-[5-(4-methoxy-3-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide(Example 30) from 4-methoxyphenyl acetone.

Example 57N-[5-(4-Chloro-3-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide

Replacing 4-fluorophenyl acetone with 4-chlorophenyl acetone in theabove procedure (Example 56) affords the title compound.

Example 58 5-(4-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine

4-(2-Acetylamino-4-methyl-thiazol-5-yl)-benzenesulfonyl chloride(Example 3a) (0.5 g, 1.5 mmol) in dioxane (2 ml) is added dropwise to astirred solution of sodium sulfite (0.378 g, 3.0 mmol) and sodiumhydrogen carbonate (0.252 g, 3.0 mmol) in water at 75° C. After 1 hourat 75° C., bromoacetic acid (0.417 g, 3.0 mmol) is added and heatingcontinued for 1 hour at 100° C. Sodium hydroxide (0.24 g, 6.0 mmol) inwater (0.25 ml) is then added and the mixture is heated with stirring at91° C. for 16 hours. The reaction mixture is allowed to cool, dilutedwith water (100 ml) and extracted with dichloromethane (3×75 ml). Thecombined organic extracts are washed with brine (75 ml), dried (MgSO₄),filtered, and the solvent removed to give the title compound. MH⁺ 268.9.

Example 591-Ethyl-3-[5-(4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea

Ethyl isocyanate (0.09 ml, 1.1 mmol) is added to a stirred solution of5-(4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 58)(0.10 g, 0.37 mmol) in dimethylformamide (1.0 ml). The mixture is heatedat 85° C. for 90 minutes followed by removal of the solvent. The residueis crystallised from ethyl acetate—methanol to afford the titlecompound. MH⁺ 340.0.

Ex. 60{3-[5-(4-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-aceticacid ethyl ester

Replacing ethyl isocyanate in Example 59 with ethyl isocyanoacetateaffords the title compound as a white solid. MH⁺ 398

Example 61{3-[5-(4-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-aceticacid

Aqueous sodium hydroxide (2M, 0.5 ml) is added to a stirred solution of{3-[5-(4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-aceticacid ethyl ester (Example 60) (0.14 g, 0.00035 mmol) in methanol (2 ml).After stirring at room temperature for 18 hours the solvent is removedand dilute HCl is added. The resulting yellow solid is removed byfiltration and recrystallised from ethanol to afford the title compound.MH⁺ 370.0

Example 623-{3-[5-(4-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-propionicacid

Replacing ethyl isocyanate in Example 59 with ethyl3-isocyanatopropionate affords{3-[5-(4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-propionicacid ethyl ester as a white solid. This is treated with aqueous sodiumhydroxide for 18 hours as described in Example 61 to afford the titlecompound as a white solid. MH⁺ 384.0

Example 63N-[5-(3-Bromo-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide

N-[5-(4-amino-3-bromo-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example7a) (1.0 g, 3.07 mmol) is converted into the corresponding sulfonylchloride by the procedure described for the conversion of aniline(Example 1a) to sulfonyl chloride (Example 3a). A sample of this crudesulfonyl chloride (1.0 g, 2.4 mmol) is dissolved in dioxane (5 ml) andthe resulting solution is added to a stirred solution of sodium sulfite(0.615 g, 4.9 mmol) and sodium hydrogen carbonate (0.41 g, 4.9 mmol) inwater (5 ml) at 75° C. After 1 hour at 75° C. bromoacetic acid (0.679 g,4.9 mmol) is added. The reaction is stirred for an additional 6 hours at75° C. When cool the mixture is diluted with water (200 ml) andextracted with dichloromethane (3×100 ml). The combined organic extractsare washed with brine (100 ml, dried (MgSO₄) and the solvent removed.Purification by chromatography on silica (EtOAc) affords the titlecompound.

Example 64N-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide64a) 3-Fluoro-4-methanesulfonyl-benzaldehyde

Methane sulfinic acid sodium salt (20.1 g, 200 mmol) is added to astirred solution of 3,4-difluorobenzaldehyde (22.5 g, 158 mmol) in dryDMSO (200 ml) at 75° C. After 2 hours the reaction is poured ontoice-water (200 ml). The precipitate is filtered, washed with water anddissolved in chloroform (400 ml). The organic extract is washed withwater (2×200 ml), dried over MgSO₄, filtered, and the solvent is removedto give the title compd as a white solid.

64b) 2-Fluoro-1-methanesulfonyl-4-(2-nitro-propenyl)-benzene

A stirred mixture of 3-fluoro-4-methanesulfonyl-benzaldehyde (Example64a) (24 g, 0.119 mol), nitroethane (70 ml, 0.97 mol) and ammoniumacetate (2.75 g, 35 mmol) is heated at reflux under argon for 24 hours.The mixture is concentrated to give an oil which is dissolved inchloroform (200 ml) and washed with water (2×200 ml), followed by brine(100 ml). The organic extract is dried (MgSO₄), filtered and the solventremoved to give the product as an orange oil. This was used immediatelyin the next step.

64c) 1-(3-Fluoro-4-methanesulfonyl-phenyl)-propan-2-one

Iron powder (25 g, 0.45 mol) is added to a stirred mixture of freshlyprepared 2-fluoro-1-methanesulfonyl-4-(2-nitro-propenyl)-benzene(Example 64b) (29 g, 0.112 mol) in THF (50 ml). Water (110 ml) is addedand the mixture is heated to 60° C. Concentrated hydrochloric acid (50ml) is added slowly over 1 h at 60-90° C. The reaction is then stirredat 100° C. for 20 hours then diluted with cold water (500 ml) andfiltered through Celite™ filter material washing with chloroform (500ml). The organic extract is washed with water (200 ml) followed by brine(200 ml). After drying (MgSO₄) the mixture is absorbed on silica andpurified by chromatography, eluting with hexane—ethyl acetate (1:1) togive the title compound.

64d)N-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide

1-(3-Fluoro-4-methanesulfonyl-phenyl)-propan-2-one (Example 64c) (1.0 g,4.34 mmol) is dissolved in dioxane (35 ml) and the solution is cooled to10° C. at which point the mixture is semi frozen. Bromine (0.067 ml, 1.2mmol, 0.3 eq.) is added slowly and the mixture is stirred for anadditional 15 min in a semi frozen state. The mixture is then allowed towarm to room temperature and the solvent is removed to give a brown oilcontaining starting material and1-bromo-1-(3-fluoro-4-methanesulfonyl-phenyl)-propan-2-one. Thismaterial is dissolved in ethanol (30 ml) and N-acetylthiourea (0.369 g,3.1 mmol) is added in one portion. The mixture is stirred at 60° C. for30 minutes then allowed to cool whereupon the product crystallised.Filtration affords the title compound as a white solid.

Example 65N-[5-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide

The title compound is prepared by an analogous procedure toN-[5-(3-fluoro-4-methane-sulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide(Example 64) by replacing 3,4-difluoro-benzaldehyde with3-fluoro-4-trifluoromethylbenzaldehyde.

Example 66N-[5-(3-Chloro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide

The title compound is prepared by an analogous procedure toN-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide(Example 64) by replacing 3,4-difluorobenzaldehyde with3,4-dichlorobenzaldehyde.

Example 67N-{5-[4-Methanesulfonyl-3-(4-methyl-piperazin-1-yl)-phenyl]-4-methyl-thiazol-2-yl}-acetamide

A stirred mixture ofN-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide(Example 64) (0.05 g, 0.15 mmol) and 1-methylpiperazine (0.1 ml, 0.9mmol) in dry DMSO (1 ml) is heated under argon at 115° C. for 1 hour.The solvent is removed and water (30 ml) is added. The product isextracted with ethyl acetate (2×30 ml) and the combined organic extractsare washed with brine (20 ml) and dried (MgSO₄). Removal of the solventand trituration with diethyl ether affords the title compound as ayellow solid.

Examples 68 to 71

These compounds, namelyN-(5-{3-[(2-dimethylamino-ethyl)-methyl-amino]-4-methane-sulfonyl-phenyl}-4-methyl-thiazol-2-yl)-acetamide,N-{5-[3-(3-dimethylamino-propylamino)-4-methanesulfonyl-phenyl]-4-methyl-thiazol-2-yl}-acetamide,N-{5-[3-(2-diethylamino-ethyl-amino)-4-methanesulfonyl-phenyl]-4-methyl-thiazol-2-yl}-acetamideandN-(5-{3-[(2-diethyl-amino-ethyl)-methyl-amino]-4-methanesulfonyl-phenyl}-4-methyl-thiazol-2-yl)-acetamiderespectively, are prepared by the same procedure as Example 67,replacing 1-methylpiperazine in this example with the appropriate amine.

Example 725-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine

This material is prepared fromN-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide(Example 64) using hydrolysis conditions described in Example 26.

Example 731-Ethyl-3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea

A mixture of5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (0.40g, 1.4 mmol) and ethyl isocyanate (0.121 ml, 1.5 mmol) in dry DMF (3 ml)is heated at 85° C. for 1 hour. The solvent is removed and the productis purified by chromatography on silica eluting with hexane—ethylacetate (1:1) to give the title compound.

Example 74 4-(2-Acetylamino-4-methyl-thiazol-5-yl)-benzoic acid 74a)3-(1-Bromo-2-oxo-propyl)-benzoic acid

A stirred solution of 4-(2-oxopropyl)benzoic acid (1.0 g, 5.6 mmol) inTHF (30 ml) at room temperature is treated with polymer supportedpyridine hydrobromide perbromide (2.8 g, 2 mmol Br₃ ⁻/g). After 3 hoursat room temperature, the reaction mixture is filtered through Celite™filter material and the solvent removed under vacuum to give the titledcompound.

74b) 4-(2-Acetylamino-4-methyl-thiazol-5-yl)-benzoic acid

A mixture of 3-(1-bromo-2-oxo-propyl)-benzoic acid (1.4 g, 5.4 mmol) andN-acetylthiourea (0.64 g, 5.4 mmol) in ethanol is stirred at 70° C. for2 hours. The reaction mixture is cooled to room temperature. Theprecipitated product is removed by and dried under vacuum to give thetitled compound.

Example 754-(2-Acetylamino-4-methyl-thiazol-5-yl)-N-(2-hydroxy-ethyl)-benzamide

To 4-(2-acetylamino-4-methyl-thiazol-5-yl)-benzoic acid (Example 74b)(0.1 g, 0.36 mmol) in DMF (1 ml) is added HATU (0.14 g, 0.36 mmol)followed by DIPEA (0.07 ml, 0.36 mmol) and ethanolamine (0.022 ml, 0.36mmol). After 5 hours, the reaction mixture is filtered and theprecipitated product is washed with ethanol and dried under vacuum togive the titled compound.

Example 764-(2-Acetylamino-4-methyl-thiazol-5-yl)-N-(2-cyano-ethyl)-benzamide

The title compound is prepared following the procedure outlined inExample 75 by replacing ethanolamine with 3-aminopropionitrile.

Agents of the invention also include compounds of formula XIX whereR^(a), R^(b), R^(c) and R¹ are as shown in the Table 2 below, the methodof preparation being described thereafter. The table also shows massspectrometry (MH⁺) data. The examples are in free form.

TABLE 2 Compounds of the invention Ex. R^(a) R^(b) R^(c) R¹ ms MH+ 77

H

440.1 78

H H

378.9 79

H H

388.0 80

H

377.0 81

H

378.0 82

H H

388.0 83 Cl

H H 303.0 84

H

391.0 85

H

391.0 86

H

405.1 87

H

391.1 88

F H

374.0 89

F H

383.0 90

H

389.0 91

F H

388.0 92

F H

421.0 93

F H

435.0 94

F H

435.0 95

F F

347.1 96

F H

402.0 97 Cl

H

388.0 98 H

H

385.0 99 Cl

H

426.0 100 Cl

399.0 101 Cl

H

440.0 102 H Cl Cl

301.5 103

H

419.8 104

H

419.8 105 Cl

H

437.8 106 Cl

H

388.6 107 Cl

H

402.7 108 Cl

H

400.7 109 Cl

H

386.7 110 Cl

H

437.7 111 Cl

H

437.8 112 Cl

H

454.9 113 Cl

H

400.7 114 Cl

H

399.9 115 Cl

H

456.9 116 Cl

H

425.9 117 Cl

H

389.9 118 Cl

H

403.9 119 Cl

H

417.9 120 Cl

H

443.9 121 Cl

H

403.9 122 Cl

H

403.9 123 Cl

H

433.9 124 Cl

H

459.0 125 Cl

H

422.9 126 Cl

H

422.9 127 Cl

H

425.9 128 Cl

H

453.9 129 Cl

H

440.9 130 Cl

H

450.9 131 Cl

H

436.9 132 Cl

H

465.9 133 Cl

H

465.9 134 Cl

H

401.9 135 Cl

H

452.9 136 Cl

H

452.9 137 Cl

H

441.9 138 Cl

H

345.8 139 Cl

H

359.9 140 Cl

H

403.97 141 Cl

H

415.97 142 Cl

H

417.94 143 Cl

H

431.99 144 Cl

H

411.9 145 Cl

H

386.95 146 Cl

H

373.9 147 Cl

H

373.9 148

H H 334.9 149

H H 377.0 150

H

430.9 151

H

435.9 152

H

449.9 153

H

402.9 154

H

444.96 155

H

458.98 156 Cl

H

389.9

Preparation of Specific Examples

Abbreviations used are as follows: DCM is dichloromethane, DIPEA isdiisopropylethylamine DME is dimethoxyethane, HATU isO-(7-azabenzotriazol-1-yl)-N,N,-N′, N′-tetramethyl-uroniumhexafluorophosphate, NBS is N-bromosuccinimide and THF istetrahydrofuran.

Example 771-(5-{3-[(2-Dimethylamino-ethyl)-methyl-amino]-4-methanesulfonyl-phenyl}-4-methyl-thiazol-2-yl)-3-ethyl-urea

A stirred mixture of1-Ethyl-3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea(Example 73) (0.05 g, 0.14 mmol) and N,N,N′-Trimethylethylenediamine(0.25 ml, 2.1 mmol) in dry DMSO (0.5 ml) is heated under argon at 120°C. for 2 hours. The solvent is in vacuo removed and the product ispurified by chromatography on silica eluting with ethanol-triethylamine(98:1) to give the titled compound. MH⁺: 440.1051

Example78N-[5-(4-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-2-tetrazol-1-yl-acetamide

5-(4-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 58)(0.08 g, 0.3 mmol) is added to a solution of HATU (0.113 g, 0.3 mmol)and 1-tetrazole acetic acid (0.039 g, 0.31 mmol) in DCM. Triethylamine(0.104 ml, 0.75 mmol) is then added and the reaction mixture is left tostir at room temperature overnight. The product is purified bychromatography on silica eluting with methanol—DCM (96:4) to give thetitled compound.

Example 79N-[5-(4-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-2-pyridin-3-yl-acetamide

This is prepared as described in Example 78 by replacing 1-tetrazoleacetic acid with 3-pyridineacetic acid.

Example 82N-[5-(4-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-2-pyridin-4-yl-acetamide

This is prepared as described in Example 78 by replacing 1-tetrazoleacetic acid with 4-pyridineacetic acid.

Example 80N-[5-(3-Imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide

A stirred mixture ofN-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide(Example 64) (0.1 g, 0.30 mmol), imidazole (0.069 g, 0.90 mmol) andcaesium carbonate (0.198 g, 0.60 mmol) in dry DMSO is heated under argonat 140° C. for 2 hours. The solvent is removed and water (30 ml) isadded. The product is extracted with ethyl acetate (2×30 ml) and thecombined organic extracts are washed with brine (20 ml) and dried(MgSO₄). Removal of the solvent and trituration with methanol affordsthe titled compound as an orange solid. MH⁺: 377.9721

Examples 81, 84 to 87, 103 and 104

The compounds, namelyN-[5-(4-methanesulfonyl-3-[1,2,4]triazol-1-yl-phenyl)-4-methyl-thiazol-2-yl]-acetamide,N-{5-[4-methanesulfonyl-3-(4-methyl-imidazol-1-yl)-phenyl]-4-methyl-thiazol-2-yl}-acetamide,N-{5-[4-methanesulfonyl-3-(2-methyl-imidazol-1-yl)-phenyl]-4-methyl-thiazol-2-yl}-acetamide,N-{5-[3-(2-ethyl-imidazol-1-yl)-4-methanesulfonyl-phenyl]-4-methyl-thiazol-2-yl}-acetamide,N-{5-[4-methanesulfonyl-3-(4-methyl-pyrazol-1-yl)-phenyl]-4-methyl-thiazol-2-yl}-acetamide,N-{5-[4-methanesulfonyl-3-(2-propyl-imidazol-1-yl)-phenyl]-4-methyl-thiazol-2-yl}-acetamideandN-{5-[3-(2-isopropyl-imidazol-1-yl)-4-methanesulfonyl-phenyl]-4-methyl-thiazol-2-yl}-acetamiderespectively, are prepared by the same procedure as Example 80 replacing1-methylpiperazine in this example with the appropriate 5-membered ringnitrogen heterocycle.

Example 835-(4-Chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine

This compound is made via an analogous procedure toN-[5-(4-Chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide(Ex. 48) by replacing N-acetylthiourea with thiourea.

Example 881-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(2-hydroxy-ethyl)-urea88a)5-(3-fluoro-4-methanesulfonyl-phenyl)-2-isocyanato-4-methyl-thiazole

5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine(Example 72) (1.74 mmol, 0.5 g) is added to acetonitrile (15 ml) andtreated with phosgene (20% solution in toluene, 6.99 mmol, 3.7 ml). Thereaction mixture is heated to reflux (85° C.) for 30 minutes. Aftercooling to room temperature the solvent is removed in vacuo to leave5-(3-fluoro-4-methanesulfonyl-phenyl)-2-isocyanato-4-methyl-thiazole asan orange solid.

88b)1-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(2-hydroxy-ethyl)-urea

5-(3-fluoro-4-methanesulfonyl-phenyl)-2-isocyanato-4-methyl-thiazole(88a)(0.58 mmol, 0.183 g) is dissolved in dioxane (5 ml) and treatedwith 2-aminoethanol (0.64 mmol, 0.039 ml) under argon. The reactionmixture is stirred and heated to 80° C. for 1 hour. The solvent is thenremoved and the residue dissolved in EtOAc and washed with water (2×20ml) followed by brine (20 ml) and dried over MgSO₄. After filtration,the solvent is removed in vacuo and the residue purified bychromatography on silica eluting with ethyl acetate—methanol (9:1) togive the title compound.

Examples 89, 91 to 94 and 96

These compounds, namely1-(2-cyano-ethyl)-3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea,1-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(3-hydroxy-propyl)-urea,1-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-pyridin-2-ylmethyl-urea,1-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-pyridin-2-yl-ethyl)-urea,1-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(2-pyridin-3-yl-ethyl)-ureaand1-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(4-hydroxy-butyl)-urearespectively are prepared by the same procedure as Example 88 replacing2-aminoethanol (part 88b) in this example with the appropriate amine.

Examples 97, 99 to 101 and 105 to 116

The compounds namely,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-propyl-urea,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-furan-2-ylmethyl-urea,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(2-cyano-ethyl)-urea,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(2,5-dimethyl-2H-pyrazol-3-yl)-urea,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-pyridin-2-ylmethyl-urea,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-isopropyl-urea,1-butyl-3-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-cyclobutyl-urea,azetidine-1-carboxylic acid[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amide,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-pyridin-4-ylmethyl-urea,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-pyridin-3-ylmethyl-urea,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(3-imidazol-1-yl-propyl)-urea,pyrrolidine-1-carboxylic acid[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amide,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-cycopropylmethyl-urea,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-urea,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-furan-3-ylmethyl-urearespectively are prepared by the same procedure as Example 88 replacing5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine(Example 72) with5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine(Example 83) and by replacing 2-aminoethanol (part 88b) with theappropriate amine.

Examples 117 to 147

The compounds namely,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(2-hydroxy-ethyl)-urea,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(3-hydroxy-propyl)-urea,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-((S)-1-hydroxymethyl-propyl)-urea,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(4-hydroxy-cyclohexyl)-urea,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-((R)-2-hydroxy-1-methyl-ethyl)-urea,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-((S)-2-hydroxy-1-methyl-ethyl)-urea,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-[2-(2-hydroxy-ethoxy)-ethyl]-urea,1-[5-(4-chloro-3-methane-sulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(3-diethylamino-propyl)-urea,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-pyridin-3-yl-urea,1-[5-(4-chloro-3-methane-sulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-pyridin-4-yl-urea,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(2-methyl-2H-pyrazol-3-yl)-urea,1-[5-(4-chloro-3-methane-sulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-urea,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(5-methyl-isoxazol-3-ylmethyl)-urea,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(4,6-dimethyl-pyridin-2-yl)-urea,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(6-methyl-pyridin-2-yl)-urea,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-((S)-2-hydroxy-2-phenyl-ethyl)-urea,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(3-hydroxymethyl-2-methyl-phenyl)-urea,1-((R)-sec-butyl)-3-[5-(4-chloro-3-methane-sulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(6-methoxy-pyridin-3-yl)-urea,1-[5-(4-chloro-3-methane-sulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(2-methoxy-pyridin-3-yl)-urea,1-[5-(4-chloro-3-methane-sulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(3,3,3-trifluoro-propyl)-urea,[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-methyl-urea,3-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-1-(2-hydroxy-ethyl)-1-methyl-urea,(R)-3-hydroxy-pyrrolidine-1-carboxylic acid[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amide,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(4-hydroxy-butyl)-urea,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(5-hydroxy-pentyl)-urea,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(1H-pyrazol-3-yl)-urea,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-cyclopropyl-urea,1-[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-ethyl-ureaand3-[5-(4-chloro-3-methane-sulfonyl-phenyl)-4-methyl-thiazol-2-yl]-1,1-dimethyl-urearespectively, are prepared by the same procedure as Example 88 replacing2-aminoethanol (part 88b) in this example with the appropriate amine andby replacing dioxane with dimethyl formamide.

Example 90N-[5-(3,4-Bis-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide

This is isolated as a minor by product in the synthesis ofN-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide(Example 64) when excess methane sulfinic acid sodium salt is added inthe first step of the synthesis (64a). The resulting aldehyde isconverted into the title compound by the procedure described in parts64b-d.

Example 95N-[5-(3,5-Difluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide

The title compound is made via an analogous procedure toN-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide(Example 64) by replacing 3,4-difluorobenzaldehyde in part 64a of theprocedure with 3,4,5-trifluorobenzaldehyde.

Example 983-[2-(3-Ethyl-ureido)-4-methyl-thiazol-5-yl]-N-(2-hydroxy-ethyl)-benzenesulfonamide98a) 1-Bromo-1-(3-nitro-phenyl)-propan-2-one

A stirred solution of 3-nitrophenylacetone (2.5 g, 14.0 mmol) in dry THF(50 ml) at room temperature is treated with polymer supported pyridinehydrobromide perbromide (7.0 g, 14.0 mmol) and left to stir overnight.The reaction mixture is then filtered and the solvent removed in vacuo.The residue is purified by chromatography on silica eluting with 1:4ethyl acetate—hexane to give the titled compound.

98b) 4-Methyl-5-(3-nitro-phenyl)-thiazol-2-ylamine

A stirred solution of 1-Bromo-1-(3-nitro-phenyl)-propan-2-one (98a) (2.4g, 9.3 mmol) in ethanol (20 ml) at room temperature is treated withthiourea (0.71 g, 9.3 mmol). The reaction mixture is heated to 70° C.for 10 minutes. The resulting precipitate is removed by filtration anddried under vacuum to give the titled compound.

98c) 1-Ethyl-3-[4-methyl-5-(3-nitro-phenyl)-thiazol-2-yl]-urea

The title compound is made via an analogous procedure to Example 88 by,first of all, replacing5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (part88a) with 4-Methyl-5-(3-nitro-phenyl)-thiazol-2-ylamine and secondly, byreplacing 2-aminoethanol with ethylamine (part 88b).

98d) 1-[5-(3-amino-phenyl)-4-methyl-thiazol-2-yl]-3-ethyl-urea

A stirred solution of1-Ethyl-3-[4-methyl-5-(3-nitro-phenyl)-thiazol-2-yl]-urea (98c) (0.55 g,1.8 mmol) in THF (25 ml) and EtOAc (50 ml) under Argon is treated with10% palladium on carbon (1.0 g). The reaction mixture was placed underan atmosphere of hydrogen for 2 hours. The mixture was then filteredthrough Celite™ filter material and the solvent removed in vacuo toyield the titled compound.

98e)3-[2-(3-Ethyl-ureido)-4-methyl-thiazol-5-yl]-N-(2-hydroxy-ethyl)-benzenesulfonamide

The titled compound is made via an analogous procedure toN-[4-methyl-5-(4-sulfamoyl-phenyl)-thiazol-2-yl]-acetamide (Example 3)by replacing N-[5-(4-amino-phenyl)-4-methyl-thiazol-2-yl]-acetamide with1-[5-(3-amino-phenyl)-4-methyl-thiazol-2-yl]-3-ethyl-urea (part 3a) andby replacing ammonia with ethanolamine (part 3b).

Example 102 N-[5-(3,5-Dichloro-phenyl)-4-methyl-thiazol-2-yl]-acetamide

The title compound is made via an analogous procedure toN-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide(Example 64d) by replacing1-(3-Fluoro-4-methanesulfonyl-phenyl)-propan-2-one with1-(3,5-Dichloro-phenyl)-propan-2-one.

Example 1485-(3-Imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine

A stirred solution ofN-[5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide(Example 80) (0.80 g, 2.13 mmol) in ethanol (15 ml) and 7M aqueous HCl(20 ml) is heated at 90° C. for 2 hours. The solution is allowed tocool, brought to pH 10 by addition of aqueous NaOH and extracted withn-butanol. The organic extract is dried (MgSO₄), the solvent is removedand the residue is triturated with ethanol to give the titled compoundas a yellow solid.

Ex. 1495-[4-Methanesulfonyl-3-(2-propyl-imidazol-1-yl)-phenyl]-4-methyl-thiazol-2-ylamine

This is prepared by an analogous procedure to Ex. 148, replacingN-[5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide(example 4) withN-{5-[4-methane-sulfonyl-3-(2-propyl-imidazol-1-yl)-phenyl]-4-methyl-thiazol-2-yl}-acetamide(Ex. 103).

Example 1501-(2-Cyano-ethyl)-3-[5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea150a) Imidazole-1-carboxylic acid[5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amide

Sodium hydride (60% dispersion in oil, 0.137 g, 3.42 mmol) is added to astirred suspension of5-(3-Imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine(148) (1.04 g, 3.1 mmol) in dry dimethylformamide (10 ml) at roomtemperature under argon. 1,1′-Carbonyl diimidazole (0.757 g, 4.67 mmol)is added and the stirred suspension is heated to 40° C. for 1 h. Thereaction mixture is cooled and the resulting solid filtered and washedwith DCM and ether to afford the title compound.

150b)1-(2-Cyano-ethyl)-3-[5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea

The titled compound is prepared by the same procedure as example 88,replacing 2-aminoethanol (part 88b) in this example with3-aminopropionitrile and replacing5-(3-fluoro-4-methanesulfonyl-phenyl)-2-isocyanato-4-methyl-thiazole(88a) with Imidazole-1-carboxylic acid[5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amide(150a)

Examples 151 to 155

These compounds, namely1-(3-hydroxy-propyl)-3-[5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea,1-(4-hydroxy-butyl)-3-[5-(3-imidazol-1-yl-4-methane-sulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea,1-cyano-3-[5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea,1-(2-cyano-ethyl)-3-[5-(3-imidazol-1-yl-4-methane-sulfonyl-phenyl)-4-methyl-thiazol-2-yl]-1-methyl-ureaand1-(2-cyano-ethyl)-1-ethyl-3-[5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urearespectively are prepared by the same procedure as Example 150 byreplacing 3-aminopropionitrile (part 150b) in that Example with theappropriate amine.

Example 156N-{5-[4-Chloro-3-(2-hydroxy-ethylsulfamoyl)-phenyl]-4-methyl-thiazol-2-yl}-acetamide

The title compound is made via an analogous procedure toN-[5-(4-Methoxy-3-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide(Example 30) by replacing 4-methoxyphenyl acetone (in example 30a) with4-chlorophenyl acetone; and ammonia with 2-amino ethanol.

Agents of the invention also include compounds of formula XIX whereR^(a), R^(b), R^(c) and R¹ are as shown in the Table 3 below, the methodof preparation being described thereafter. The table also shows massspectrometry (MH⁺) data. The examples are in free form.

TABLE 3 Compounds of the invention Ex. R^(a) R^(b) R^(c) R¹ m/s MH+ 157

H

411 158

—CF₃ H

409 159

F H

343.1 160

H

391.2 161 F —OCH₃ H

281 162 Cl

H

402.2 163 Cl

—H

508.3 164

F H

444 165

F H

430 166

—CF₃ H

480 167

—CF₃ H

494 168

H

478 169

H

492 170 Cl

H

446.2 171

Cl Cl

509.2 172

F H

415.2 173

H H

413.2 174 Cl

H

458.3 175

—CN H

336.1 176 H

H

412.1 177

F H

330 178

F H

453 179

F H

453.3 180

F H

439.03 181

F H

439.07

Preparation of Specific Examples Example 1572-Chloro-N-[5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide

5-(3-Imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine(Example 148) (0.537 g, 1.60 mmol) and chloroacetyl chloride (5 ml) areheated together for 2 hours. The reaction mixture is allowed to cool toroom temperature and the solid filtered and washed with saturated sodiumbicarbonate solution (3×100 ml) and water (2×50 ml) to yield the titledcompound.

Example 158N-[5-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-yl]-2-methoxy-acetamide158a)5-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-ylamine

The title compound is prepared by an analogous procedure toN-[5-(3-fluoro-4-methane-sulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide(Example 64) by replacing 3,4-difluorobenz-aldehyde with3-fluoro-4-trifluoromethylbenzaldehyde (part 64a) and by replacingN-acetal-thiourea with thiourea (part 64d).

158b)N-[5-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-yl]-2-methoxy-acetamide

5-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-ylamine(158a) (0.1 g, 0.3 mmol) is added to a solution of HATU (0.226 g, 0.6mmol), methoxyacetic acid (0.046 ml, 0.6 mmol) and DIPEA (0.1 ml, 0.6mmol) in DMF (7.5 ml). The reaction mixture was left to stir for 3 daysat room temperature. The reaction mixture is filtered through basicalumina. The solvent is removed in vacuo and the product is purified bychromatography on silica eluting with ethyl acetate-hexane (3:1) to givethe titled compound.

Example 159N-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-propionamide

5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine(Example 72) (1 g, 3.39 mmol) is suspended in propionic anhydride (12.5ml) and heated to 70° C. for 1 hour. The reaction mixture is cooled toroom temperature and the solvent removed in vacuo. The solid istriturated with ether to yield the titled compound.

Example 160N-[5-(3-Imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-propionamide

The title compound is prepared via an analogous procedure toN-[5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide(Example 80) by replacingN-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamidein this example withN-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-propionamide(159).

Example 161N-[5-(4-Fluoro-3-methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide 161a)1-(4-Fluoro-3-methoxy-phenyl)-propan-2-one

The title compound is prepared via an analogous procedure to1-((3-fluoro-4-methanesulfonyl-phenyl)-propan-2-one (64c) (steps64b-64c) by replacing 3-fluoro-4-methanesulfonyl-benzaldehyde in step64b with 4-fluoro-3-methoxy-benzaldehyde.

161b) 1-bromo-1-(4-fluoro-3-methoxy-phenyl)-propan-2-one

A stirred solution of 1-(4-fluoro-3-methoxy-phenyl)-propan-2-one (161a)(0.5 g, 2.74 mmol) in dry THF (5 ml) is treated dropwise with a solutionof 2-carboxyethyltriphenylphosphonium perbromide (1.66 g, 2.88 mmol) inTHF. The reaction mixture is allowed to stir at room temperature for 1.5hours and then filtered. The filtrate is concentrated in vacuo to yieldthe titled compound.

161c) N-[5-(4-Fluoro-3-methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide

1-Bromo-1-(4-fluoro-3-methoxy-phenyl)-propan-2-one (161b) (0.72 g, 2.74mmol) is dissolved in ethanol (20 ml) and N-acetylthiourea (0.324 g,2.72 mmol) is added in one portion. The mixture is stirred at 80° C.overnight then allowed to cool whereupon the product crystallised.Filtration affords the title compound as a white solid.

Example 162 3-Hydroxy-azetidine-1-carboxylic acid[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amide162a) 1-Benzhydryl-3-(tert-butyl-diphenyl-silanyloxy)-azetidine

A stirred solution of 1-Benzhydrylazetan-3-ol (2.0 g, 8.4 mmol) in DMF(20 ml) at 0° C. is treated with imidazole (0.57 g, 8.4 mmol) andt-butylchlorodiphenyl silane (2.31 g, 8.4 mmol). The reaction mixture isallowed to warm up to room temperature and stirred overnight. Themixture is poured into water (250 ml) and extracted with EtOAc (3×100ml). The combined organic extracts are washed with water (2×100 ml),brine (100 ml) and dried over MgSO₄. The solvent is removed in vacuo toyield the titled compound.

162b) 3-(tert-Butyl-diphenyl-silanyloxy)-azetidine

A stirred solution of1-benzhydryl-3-(tert-butyl-diphenyl-silanyloxy)-azetidine (162a) (4.0 g,8.4 mmol) in DCE (60 ml) at room temperature is treated with1-chloroethylchloroformate (1.2 ml, 10.9 mmol) and the reaction mixtureis heated to 80° C. After 2 hours, the solvent is removed in vacuo andthe residue is dissolved in methanol (60 ml) and heated to reflux. After1 h the reaction mixture is poured into water (250 ml), acidified withhydrochloric acid (1M solution) and washed with EtOAc (3×75 ml). Theaqueous solution is basified with saturated sodium bicarbonate solutionand extracted with EtOAc (3×75 ml). The combined organic layers arewashed with water (2×50 ml), brine (50 ml), dried over MgSO₄. Thesolvent is removed in vacuo to yield the titled compound.

162c) 3-(tert-Butyl-diphenyl-silanyloxy)-azetidine-1-carboxylic acid[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazole-2-yl]amide

A stirred solution of5-(4-chloro-3-methanesulfonyl-phenyl)-2-isocyanato-4-methyl-thiazole[prepared by the same procedure as example 88a replacing5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine(Example 72) in this example with5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine(Example 83)] (0.2 g, 0.61 mmol) in DMF is treated with3-(tert-butyl-diphenyl-silanyloxy)-azetidine (162b) (0.25 g, 0.8 mmol)and the reaction mixture is heated to 120° C. After 30 minutes, thereaction is complete. The product is purified by chromatography onsilica eluting with ethyl acetate-hexane (1:2) to give the titledcompound.

162d) 3-Hydroxy-azetidine-1-carboxylic acid[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amide

A stirred solution of3-(tert-butyl-diphenyl-silanyloxy)-azetidine-1-carboxylic acid[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazole-2-yl]amide(162c) (0.15 g, 0.23 mmol) in THF (2 ml) at room temperature is treatedwith tetrabutylammonium fluoride (1.0 M in THF, 0.23 ml, 0.23 mmol).After 30 minutes, the reaction was complete. Purification by preparativeLC-MS affords the titled compound.

Example 1631-[5-(4-Chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(6-morpholin-4-yl-pyridin-3-yl)-urea

The title compound is prepared by the same procedure as1-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(2-hydroxy-ethyl)-urea(Example 88) replacing5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine(Example 72) with5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine(Example 83) and by replacing 2-aminoethanol (part 88b) with6-morpholinopyridin-3-amine.

Example 1644-{3-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-butyricacid ethyl ester

5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine(Example 72), (0.1 g, 0.31 mmol) DIPEA (0.039 ml, 0.34 mmol),ethyl-4-isocyanatobutyrate (0.046 ml, 0.31 mmol) in DCM (2 ml) areheated together at reflux overnight. The reaction mixture is dilutedwith DCM (20 ml) and washed with 1M hydrochloric acid (15 ml), water(2×15 ml), brine (15 ml), dried over MgSO₄, filtered and concentrated invacuo to yield the titled compound as an off white solid.

Example 1653-{3-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-propionicacid ethyl ester

The title compound is prepared by the same procedure as4-{3-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-butyricacid ethyl ester (Example 164) by replacing ethyl-4-isocyanatobutyratewith 3-isocyanato-propionic acid ethyl ester.

Example 1663-{3-[5-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-propionicacid ethyl ester

The title compound is prepared by the same procedure as4-{3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-butyricacid ethyl ester (Example 164) by replacing5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine(Example 72) with5-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-ylamine(158a) and replacing ethyl-4-isocyanatobutyrate with3-isocyanato-propionic acid ethyl ester.

Example 1674-{3-[5-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-butyricacid ethyl ester

The title compound is prepared by the same procedure as4-{3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-butyricacid ethyl ester (Example 164) by replacing5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine(Example 72) with5-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-ylamine(158a).

Example 1683-{3-[5-(3-Imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-propionicacid ethyl ester

The title compound is prepared by the same procedure as4-{3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-butyricacid ethyl ester (Example 164) by replacing5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine(Example 72) with5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine(Example 148) and replacing ethyl-4-isocyanatobutyrate with3-isocyanato-propionic acid ethyl ester.

Example 1694-{3-[5-(3-Imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-butyricacid ethyl ester

The title compound is prepared by the same procedure as4-{3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-butyricacid ethyl ester (Example 164) by replacing5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine(Example 72) with5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine(Example 148).

Example 1703-{3-[5-(4-Chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-propionicacid ethyl ester

The title compound is prepared by the same procedure as4-{3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-butyricacid ethyl ester (Example 164) by replacing5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine(Example 72) with5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine(Example 83) and replacing ethyl-4-isocyanatobutyrate with3-isocyanato-propionic acid ethyl ester.

Example 1713-{3-[5-(3,5-Dichloro-4-dimethylsulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-propionicacid ethyl ester 171a)N-[5-(3,5-Dichloro-4-dimethylsulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide

The title compound is prepared by an analagous procedure toN-[5-(3,5-dichloro-4-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide(Example 6) by replacing ammonia with dimethylamine.

171b)4-(2-Amino-4-methyl-thiazol-5-yl)-2,6-dichloro-N,N-dimethyl-benzenesulfonamide

The title compound is prepared by the same procedure as4-(2-amino-4-methyl-thiazol-5-yl)-2,6-dichloro-benzenesulfonamide(Example 26) by replacingN-[5-(3,5-dichloro-4-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide(Example 6) withN-[5-(3,5-dichloro-4-dimethylsulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide(171a).

171c)3-{3-[5-(3,5-Dichloro-4-dimethylsulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-ureido)}-propionicacid ethyl ester

The title compound is prepared by the same procedure as4-{3-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-butyricacid ethyl ester (Example 164) by replacing5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine(Example 72) with4-(2-amino-4-methyl-thiazol-5-yl)-2,6-dichloro-N,N-dimethyl-benzenesulfonamide(171b) and replacing ethyl-4-isocyanatobutyrate with3-isocyanato-propionic acid ethyl ester.

Example 1724-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylcarbamoyl]-butyricacid methyl ester

Methyl-4-(chloroformyl) butyrate (4.0 mmol) is added to a stirredsolution of5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine(Example 72) (0.77 g, 2.69 mmol) and heated to 60° C. for 1.5 hours. Thereaction mixture is allowed to cool to room temperature and the solventremoved in vacuo. The residue is washed with saturated sodiumbicarbonate solution (2×50 ml) and water (1×50 ml). The product isextracted with ethyl acetate (2×50 ml) and the combined organic extractsdried (MgSO₄). Removal of the solvent followed by recrystallisation fromethyl acetate affords the tided compound.

Example 1733-{3-[5-(4-Dimethylsulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-propionicacid

To a stirred solution of3-{3-[5-(4-dimethylsulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-propionicacid ethyl ester (Example 24) in methanol (5 ml) is added dropwisesodium hydroxide (2M, 3 ml) over 2 minutes. The reaction mixture isheated at reflux overnight and then allowed to cool to room temperature.The mixture is neutralised with hydrochloric acid (2M, 3 ml) and theresulting precipitate is filtered, washed with water (20 ml) and driedin vacuo to yield the titled compound.

Example 1741-{5-[4-Chloro-3-(4-methyl-2-piperazine-1-sulfonyl)-phenyl]-4-methyl-thiazol-2-yl}-3-ethyl-urea174a) 2-Chloro-5-(2-oxopropyl)-benzenesulphonyl chloride

To chlorosulfonic acid (25 ml, excess) cooled at −10° C. is addeddropwise 4-chlorophenyl acetone (1.0 g, 5.93 mmol). The temperature iskept below 0° C. throughout the addition. The reaction mixture is thenleft to warm up to room temperature overnight. The reaction mixture ispoured carefully onto ice (1500 ml). Once the ice is melted, the aqueouslayer is extracted with dichloromethane (3×250 ml). The combined organiclayers are dried over MgSO₄, filtered and concentrated to afford thetitled compound as an off-white solid.

174b)1-[4-Chloro-3-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propan-2-one

2-Chloro-5-(2-oxopropyl)-benzenesulphonyl chloride (174a) (2.0 g, 7.5mmol) is dissolved in dioxan (50 ml) with stirring. Sodium carbonate(7.5 ml, 2M solution, 2 eq.) is added followed by 1-methyl piperazine(0.75 g, 7.5 mmol). After 30 min the reaction mixture is poured ontowater (250 ml) and extracted with ethyl acetate (3×100 ml). The combinedorganic extracts are washed with water (2×100 ml) followed by brine (100ml) and dried (MgSO₄). After filtration the solvent is removed and theproduct is purified by chromatography on silica, eluting with ethylacetate/hexane (1:2) to afford the titled compound.

174c)1-Bromo-1-[4-chloro-3-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propan-2-one

A stirred solution of1-[4-chloro-3-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propan-2-one(174b) (0.5 g, 1.22 mmol) in dry THF (5 ml) is treated dropwise with asolution of 2-carboxyethyltriphenylphosphonium perbromide (0.84 g, 1.44mmol) in THF. The reaction mixture is allowed to stir at roomtemperature for 1.5 hours and then filtered. The filtrate isconcentrated in vacuo to yield the titled compound.

174d)5-[4-Chloro-3-(4-methyl-piperazine-1-sulfonyl)-phenyl]-4-methyl-thiazol-2-ylamine

The title compound is prepared as an HBr salt by the same procedure asN-[5-(4-fluoro-3-methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide (161c)by replacing 1-bromo-1-(4-fluoro-3-methoxy-phenyl)-propan-2-one (161b)with1-bromo-1-[4-chloro-3-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propan-2-one(171c) and N-acetylthiourea with thiourea.

174e)1-{5-[4-Chloro-3-(4-methyl-piperazine-1-sulfonyl)-phenyl]-4-methyl-thiazol-2-yl}-3-ethyl-urea

A stirred solution of5-[4-Chloro-3-(4-methyl-piperazine-1-sulfonyl)-phenyl]-4-methyl-thiazol-2-ylaminehydrobromide (174d) (0.1 g, 0.26 mmol) in DMF (1 ml) at room temperatureis treated with DIPEA (0.07 g, 0.52 mmol) and ethyl isocyanate (0.025ml, 0.33 mmol). The reaction mixture is heated to 120° C. for 1 hour andthen allowed to cool to room temperature. Purification by preparativeLC-MS affords the titled compound.

Example 175N-[5-(3-Cyano-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide

The titled compound was prepared by an identical procedure toN-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide(Example 64) replacing 3,4-difluorobenzaldehyde in this procedure with2-fluoro-5-formylbenzonitrile.

Examples 1763-{3-[5-(3-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-propionicacid ethyl ester 176a)1-(4-Chloro-3-methanesulphonyl-phenyl)-propan-2-one

A stirred solution of 2-Chloro-5-(2-oxo-propyl)-benzenesulphonylchloride (prepared as described in Example 174a) (20.0 g, 74.9 mmol) indioxane (300 ml) at room temperature is treated with a solution ofsodium sulphite (18.9 g, 150 mmol) and sodium hydrogen carbonate (12.6g, 150 mmol) in water (200 ml). The reaction mixture is heated to 75° C.for 10 minutes and then allowed to cool to room temperature. The solventis removed in vacuo and the residue dissolved in DMF (200 ml). Thesolution is stirred at room temperature and treated with iodomethane(21.2 g, 150 mmol). After stirring for 20 minutes, the reaction mixtureis diluted with water (1000 ml) and extracted with ethyl acetate (3×250ml). The combined organic layers are washed with water (2×200 ml), brine(100 ml), dried over MgSO₄ and concentrated in vacuo to yield the titledcompound.

176b) 1-(3-Methanesulphonyl-phenyl)-propan-2-one

A solution of 1-(4-chloro-3-methanesulphonyl-phenyl)-propan-2-one (5.49g, 22.28 mmol) in methanol (250 ml) is stirred under hydrogen in thepresence of 10% Pd on carbon (3 g) for 2 hours. The reaction mixture isfiltered and concentrated in vacuo to yield a yellow oil of the titledcompound.

176c) 1-Bromo-1-(3-methanesulphonyl-phenyl)-propanone

A stirred solution of 1-(3-methanesulphonyl-phenyl)-propan-2-one (176b)(0.25 g, 1.18 mmol) in dioxane (10 ml) at 5° C. is treated with bromine(0.131 g, 0.82 mmol) added in two portions. The reaction is stirred andallowed to warm up to room temperature. The solvent is removed in vacuoto yield an orange oil of the titled compound.

176d) 5-(3-Methanesulphonyl-phenyl)-4-methyl-thiazol-2-ylaminehydrobromide

A stirred solution of 1-bromo-1-(3-methanesulphonyl-phenyl)-propanone(176c) (0.32 g, 1.01 mmol) is treated with thiourea (0.067 g, 0.88 mmol)added in one portion. The reaction mixture is allowed to stir at roomtemperature over two days. The product precipitates out and is filteredto yield the title compound as while solid.

176e)3-{3-[5-(3-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-propionicacid ethyl ester

A stirred suspension of5-(3-methanesulphonyl-phenyl)-4-methyl-thiazol-2-ylamine hydrobromide(176d) (0.172 g, 0.64 mmol) in DCM (15 ml) is treated with Hunigs base(0.45 ml, 2.36 mmol) followed by ethyl-3-isocyanatopropionate (0.092 g,0.64 mmol). The reaction mixture is stirred and heated to 60° C. for 10hours and then the solvent in removed in vacuo. The product is purifiedby chromatography on silica to give the titled compound

Examples 177[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea 177a)Imidazole-1-carboxylic acid[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amide

The title compound is prepared by the same procedure asimidazole-1-carboxylic acid[5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amide(Example 150a) by replacing5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine(Example 148) with5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine(Example 72)

177b) [5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea

The title compound is prepared by the same procedure as1-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(2-hydroxy-ethyl)-urea(Example 88) by replacing 2-aminoethanol (part 88b) in this example withammonia.

Examples 1781-[2-(5-Ethyl-oxazol-2-yl)-ethyl]-3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea

The title compound is prepared by the same procedure as-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea(Example 177) by replacing ammonia (part 177b) with the hydrochloridesalt of 2-(5-Ethyl-oxazol-2-yl)-ethylamine (details of preparationprocedure follows below), by replacing dioxane with DMF and by usingtriethylamine as a base.

2-(5-Ethyl-oxazol-2-yl)-ethylamine) Step 1)[2-(2-Hydroxy-butylcarbamoyl)-ethyl]-carbamic acid benzyl ester

A mixture comprising Z-Beta-Ala-OH (9.0 g, 40.3 mmol), EDCI.HCl (10.0 g,52.4 mmol), hyrdoxybenzotriazole (5.45 g, 40.3 mmol), triethylamine (7.3ml, 52.4 mmol) in DCM (150 ml) is stirred at 0° C. for 30 minutes.1-Amino-2-butanol (4.2 ml, 44.3 mmol) is added in one portion andstirring is continued for 1 hour. The reaction mixture is diluted withwater (150 ml) and extracted with dichloromethane (2×150 ml) The organiclayers are combined, dried over MgSO₄, filtered and concentrated invacuo to yield a crude white solid. The product is purified bychromatography on silica eluting with ethanol-ethyl acetate (1:10) togive the titled compound.

Step 2) [2-(2-Oxo-butylcarbamoyl)-ethyl]-carbamic acid benzyl ester

To a stirred solution of oxalyl chloride (2 M in DCM) (13.35 ml, 26.5mmol) in dry DCM at −78° C. is added dropwise DMSO (2.5 ml, 35.4 mmol).After stirring for 15 minutes, the reaction mixture is treated with asolution of [2-(2-hydroxy-butylcarbamoyl)-ethyl]-carbamic acid benzylester (step 1) (6.5 g, 22.1 mol) in dry DCM (40 ml). Triethylamine (13ml) is added after 1 hour and after stirring at −78° C. for 90 minutes,the reaction mixture is allowed to warm to room temperature. Thereaction is diluted with DCM (100 ml) and washed with HCl (1M, 200 ml),saturated sodium bicarbonate solution (200 ml), water (200 ml) and brine(200 ml). The organic portion is dried over MgSO₄, filtered andconcentrated in vacuo to yield the titled compound as a white solid.

Step 3) [2-(5-Ethyl-oxazol-2-yl)-ethyl]-carbamic acid benzyl ester

To a stirred suspension of polymer supported triphenylphosphene (19.6 g,58.9 mmol) in DCM (250 ml) is added iodine (14.95 g, 58.9 mmol). Afterstirring at room temperature for 10 minutes, the mixture is treated withtriethylamine (16.4 ml, 117.5 mmol) followed by a solution of[2-(2-oxo-butylcarbamoyl)-ethyl]-carbamic acid benzyl ester (step 2)(6.88 g, 23.5 mmol) in DCM (50 ml). The reaction mixture is stirredovernight and then filtered through celite, washed through with DCM (500ml) and the solvent removed in vacuo to yield the titled compound as abrown solid.

Step 4) 2-(5-Ethyl-oxazol-2-yl)-ethylamine (hydrochloride salt)

A solution of [2-(5-ethyl-oxazol-2-yl)-ethyl]-carbamic acid benzyl ester(step 3) (0.41 g, 1.49 mmol), 2M HCl (0.75 ml) in ethanol (40 ml) isstirred under hydrogen in the presence of 10% Pd on carbon (0.041 g) for5 hours. The reaction mixture is filtered and concentrated in vacuo toyield the titled compound.

Examples 1791-[2-(4-Ethyl-oxazol-2-yl)-ethyl]-3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea

The title compound is prepared by the same procedure as1-[2-(5-ethyl-oxazol-2-yl)-ethyl]-3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea(Example 178) by replacing 2-(5-ethyl-oxazol-2-yl)-ethylaminehydrochloride (step 4) with the hydrochloride salt of2-(4-ethyl-oxazol-2-yl)-ethylamine. This is prepared by the sameprocedure as 2-(5-ethyl-oxazol-2-yl)-ethylamine hydrochloride (step 4)by replacing 1-amino-2-butanol (step 1) with 2-amino-1-butanol.

Example 1801-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-[2-(5-methyl-oxazol-2-yl)-ethyl]-urea

The title compound is prepared by the same procedure as1-[2-(5-ethyl-oxazol-2-yl)-ethyl]-3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea(Example 178) by replacing 2-(5-ethyl-oxazol-2-yl)-ethylaminehydrochloride (step 4) with the hydrochloride salt of2-(5-methyl-oxazol-2-yl)ethylamine. This is prepared by the sameprocedure as 2-(5-ethyl-oxazol-2-yl)ethylamine hydrochloride (step 4) byreplacing 1-amino-2-butanol (step 1) with 1-amino-2-propanol.

Example 1811-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-[2-(4-methyl-oxazol-2-yl)-ethyl]-urea

The title compound is prepared by the same procedure as1-[2-(5-ethyl-oxazol-2-yl)-ethyl]-3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea(Example 178) by replacing 2-(5-ethyl-oxazol-2-yl)-ethylaminehydrochloride (step 4) with the hydrochloride salt of2-(4-methyl-oxazol-2-yl)ethylamine. This is prepared by the sameprocedure as 2-(5-ethyl-oxazol-2-yl)-ethylamine hydrochloride (step 4)by replacing 1-amino-2-butanol (step 1) with 2-amino-1-propanol.

1. A compound of formula I

in free or salt form, wherein R¹ is C₁-C₈-alkylcarbonyl optionallysubstituted by the group consisting of, hydroxy, C₁-C₈-alkylamino,carboxy, C₁-C₈-alkoxycarbonyl, nitrile, phenyl, C₁-C₈-haloalkyl,C₁-C₈-alkyl optionally substituted by hydroxy, C₃-C₈-cycloalkyloptionally substituted by hydroxy, C₁-C₈-alkoxy optionally substitutedby hydroxy, phenyl substituted by hydroxy or C₁-C₈-alkyl and, 5- or6-membered unsaturated heterocyclic ring having one or more ring heteroatoms selected from the group consisting of oxygen, nitrogen andsulphur, that heterocyclic ring being optionally substituted by hydroxy,C₁-C₈-alkyl or C₁-C₈-alkoxy, R² is C₁-C₃-alkyl or halogen; R⁵ ishydrogen or halogen; R³ is hydrogen, hydroxy, amino, —SOR⁸, —SO₂R⁸,—SO₂NH₂, —SO₂NR⁹R¹⁰, —COR⁸, —CONHR⁸, —NHSO₂R⁸, nitrile, carboxy, —OR⁸ orC₁-C₈-haloalkyl; R⁴ is —NR¹²R¹³; R⁸ is C₁-C₈-alkyl or C₃-C₈-cycloalkyl,optionally substituted by halogen, hydroxy, C₁-C₈-alkoxy, nitrile,amino, C₁-C₈-alkylamino or di(C₁-C₈-alkyl)amino; R⁹ is C₁-C₈-alkyl orC₃-C₈-cycloalkyl, optionally substituted by hydroxy, C₁-C₈-alkoxy,nitrile, amino, C₁-C₈-alkylamino, di(C₁-C₈-alkyl)amino or a 5- or6-membered heterocyclic ring having one or more ring hetero atomsselected from the group consisting of oxygen, nitrogen and sulphur, thatring being optionally substituted by C₁-C₈-alkyl; R¹⁰ is hydrogen orC₁-C₈-alkyl; or R⁹ and R¹⁰ together with the nitrogen atom to which theyare attached form a 5- or 6-membered heterocyclic ring that contains oneor more further hetero atoms selected from the group consisting ofoxygen, nitrogen and sulphur, that ring being optionally substituted byC₁-C₈-alkyl; and R¹² and R¹³ together with the nitrogen atom to whichthey are attached form a 5- or 6-membered heterocyclic ring thatcontains one or more further hetero atoms selected from the groupconsisting of oxygen, nitrogen and sulphur, that ring being optionallysubstituted by C₁-C₈-alkyl.
 2. A compound according to claim 1 whereinR¹ is C₁-C₈-alkylcarbonyl optionally substituted by the group consistingof hydroxy, carboxy, C₁-C₈-alkoxycarbonyl, nitrile, phenyl,C₁-C₈-haloalkyl, C₁-C₈-alkyl optionally substituted by hydroxy,C₁-C₈-alkoxy optionally substituted by hydroxy, and a 5- or 6-memberedunsaturated heterocyclic ring having one or more ring hetero atomsselected from the group consisting of oxygen, nitrogen and sulphur, thatring being optionally substituted by C₁-C₈-alkyl, R² is C₁-C₃-alkyl; R⁵is hydrogen or halogen; R³ is hydrogen, hydroxy, amino, —SO₂R⁸, —SO₂NH₂,—SO₂NR⁹R¹⁰, —NHSO₂R⁸, cyano, carboxy, —OR⁸ or C₁-C₄-haloalkyl; R⁴ is—NR¹²R¹³; R⁸ is C₁-C₈-alkyl; R⁹ is C₁-C₈-alkyl optionally substituted byhydroxy, C₃-C₈-cycloalkyl optionally substituted by hydroxy,C₁-C₈-alkoxy, nitrile, di(C₁-C₈-alkyl)amino or a 5- or 6-memberedheterocyclic ring having one or more ring hetero atoms selected from thegroup consisting of oxygen and nitrogen, that ring being optionallysubstituted by C₁-C₈-alkyl; R¹⁰ is hydrogen or C₁-C₈-alkyl; or R⁹ andR¹⁰ together with the nitrogen atom to which they are attached form a 5-or 6-membered heterocyclic ring that contains one or more further heteroatoms selected from the group consisting of oxygen and nitrogen, thatring being optionally substituted by C₁-C₈-alkyl; and R¹² and R¹³together with the nitrogen atom to which they are attached form a 5- or6-membered heterocyclic ring that contains one or more further heteroatoms selected from the group consisting of oxygen and nitrogen, thatring being optionally substituted by C₁-C₈-alkyl.
 3. A compoundaccording to claim 2, in free or salt form, wherein R¹ isC₁-C₄-alkylcarbonyl optionally substituted by the group consisting ofhydroxy, carboxy, C₁-C₄-alkoxycarbonyl, nitrile, phenyl,C₁-C₄-haloalkyl, C₁-C₄-alkyl optionally substituted by hydroxy,C₁-C₄-alkoxy optionally substituted by hydroxy, and a 5- or 6-memberedunsaturated heterocyclic ring having one or more ring hetero atomsselected from the group consisting of oxygen, nitrogen and sulphur, thatheterocyclic ring being optionally substituted by C₁-C₄-alkyl, R² isC₁-C₃-alkyl; R⁵ is hydrogen or halogen; R³ is hydrogen, hydroxy, amino,SO₂R⁸, SO₂NH₂, SO₂NR⁹R¹⁰, NHSO₂R⁸, cyano, carboxy, OR⁸ orC₁-C₄-haloalkyl; R⁴ is —NR¹²R¹³; R⁸ is C₁-C₄-alkyl; R⁹ is C₁-C₄-alkyloptionally substituted by hydroxy, C₃-C₅-cycloalkyl optionallysubstituted by hydroxy, C₁-C₄-alkoxy, nitrile, di(C₁-C₄-alkyl)amino or a5- or 6-membered heterocyclic ring having one or more ring hetero atomsselected from the group consisting of oxygen and nitrogen, that ringbeing optionally substituted by C₁-C₄-alkyl; R¹⁰ is hydrogen orC₁-C₄-alkyl; or R⁹ and R¹⁰ together with the nitrogen atom to which theyare attached form a 5- or 6-membered heterocyclic ring that contains oneor more further hetero atoms selected from the group consisting ofoxygen and nitrogen, that ring being optionally substituted byC₁-C₄-alkyl; and R¹² and R¹³ together with the nitrogen atom to whichthey are attached form a 5- or 6-membered heterocyclic ring thatcontains one or more further hetero atoms selected from the groupconsisting of oxygen and nitrogen, that ring being optionallysubstituted by C₁-C₄-alkyl.
 4. A compound of formula I according toclaim 1 in free or salt form, wherein R¹ is C₁-C₈-alkylcarbonyloptionally substituted by the group consisting of hydroxy,C₁-C₈-alkylamino, carboxy, C₁-C₈-alkyl optionally substituted by thegroup consisting of hydroxy, C₃-C₈-cycloalkyl optionally substituted byhydroxy, C₁-C₈-alkoxy optionally substituted by hydroxy,C₁-C₈-alkoxycarbonyl, nitrile, or phenyl optionally substituted byhydroxy or C₁-C₈-alkyl, and a 5- or 6-membered unsaturated heterocyclicring having one or more ring hetero atoms selected from the groupconsisting of oxygen, nitrogen and sulphur, that heterocyclic ring beingoptionally substituted by hydroxy, C₁-C₈-alkyl or C₁-C₈-alkoxy, R² isC₁-C₃-alkyl or halogen; R⁵ is hydrogen or halogen; R³ is hydrogen,hydroxy, amino, —SOR⁸, —SO₂R⁸, —SO₂NH₂, —SO₂NR⁹R¹⁰, —COR⁸, —CONHR⁸,NHSO₂R⁸, nitrile, carboxy, —OR⁸ or C₁-C₈-haloalkyl; R⁴ is —NR¹²R¹³; R⁸is C₁-C₈-alkyl or C₃-C₈-cycloalkyl, optionally substituted by halogen,hydroxy, C₁-C₈-alkoxy, nitrile, amino, C₁-C₈-alkylamino ordi(C₁-C₈-alkyl)amino; R⁹ is C₁-C₈-alkyl or C₃-C₈-cycloalkyl, optionallysubstituted by hydroxy, C₁-C₈-alkoxy, nitrile, amino, C₁-C₈-alkylamino,di(C₁-C₈-alkyl)amino or a 5- or 6-membered heterocyclic ring having oneor more ring hetero atoms selected from the group consisting of oxygen,nitrogen and sulphur, that ring being optionally substituted byC₁-C₈-alkyl; R¹⁰ is hydrogen or C₁-C₈-alkyl; or R⁹ and R¹⁰ together withthe nitrogen atom to which they are attached form a 5- or 6-memberedheterocyclic ring that contains one or more further hetero atomsselected from the group consisting of oxygen, nitrogen and sulphur, thatring being optionally substituted by C₁-C₈-alkyl; and R¹² and R¹³together with the nitrogen atom to which they are attached form a 5- or6-membered heterocyclic ring that contains one or more further heteroatoms selected from the group consisting of oxygen, nitrogen andsulphur, that ring being optionally substituted by C₁-C₈-alkyl.
 5. Acompound according to claim 4 wherein R¹ is C₁-C₈-alkylcarbonyloptionally substituted by the group consisting of hydroxy, carboxy,C₁-C₈-alkyl optionally substituted by hydroxy, C₃-C₈-cycloalkyloptionally substituted by hydroxy, C₁-C₈-alkoxy optionally substitutedby hydroxy, C₁-C₈-alkoxycarbonyl, nitrile, and phenyl optionallysubstituted by hydroxy or C₁-C₈-alkyl; R² is C₁-C₃-alkyl; R⁵ is hydrogenor halogen; R³ is hydrogen, hydroxy, amino, —SO₂R⁸, —SO₂NH₂, —SO₂NR⁹R¹⁰,—NHSO₂R⁸, cyano, carboxy, —OR⁸ or C₁-C₄-haloalkyl; R⁸ is C₁-C₈-alkyl; R⁹is C₁-C₈-alkyl optionally substituted by hydroxy, C₃-C₈-cycloalkyloptionally substituted by hydroxy, C₁-C₈-alkoxy, nitrile,di(C₁-C₈-alkyl)amino or a 5- or 6-membered heterocyclic ring having oneor more ring hetero atoms selected from the group consisting of oxygenand nitrogen, that ring being optionally substituted by C₁-C₈-alkyl; R¹⁰is hydrogen or C₁-C₈-alkyl; or R⁹ and R¹⁰ together with the nitrogenatom to which they are attached form a 5- or 6-membered heterocyclicring that contains one or more further hetero atoms selected from thegroup consisting of oxygen and nitrogen, that ring being optionallysubstituted by C₁-C₈-alkyl; and R¹² and R¹³ together with the nitrogenatom to which they are attached form a 5- or 6-membered heterocyclicring that contains one or more further hetero atoms selected from thegroup consisting of oxygen and nitrogen, that ring being optionallysubstituted by C₁-C₈-alkyl.
 6. A compound of formula I according toclaim 1, in free or salt form, wherein R¹ is C₁-C₈-alkylcarbonyloptionally substituted by the group consisting of carboxy, C₁-C₃-alkoxy,C₁-C₈-alkoxycarbonyl, or nitrile; R² is C₁-C₃-alkyl or halogen; R⁵ ishydrogen or halogen; R³ is hydrogen, hydroxy, amino, SOR⁸, SO₂R⁸,SO₂NH₂, SO₂NR⁹R¹⁰, COR⁸, CONHR⁸, NHSO₂R⁸, nitrile, carboxy, OR⁸ orC₁-C₈-haloalkyl; R⁴ is NR¹²R¹³; R⁸ is C₁-C₈-alkyl or C₃-C₈-cycloalkyl,optionally substituted by halogen, hydroxy, C₁-C₈-alkoxy, nitrile,amino, C₁-C₈-alkylamino or di(C₁-C₈-alkyl)amino; R⁹ is C₁-C₈-alkyl orC₃-C₈-cycloalkyl, optionally substituted by hydroxy, C₁-C₈-alkoxy,nitrile, amino, C₁-C₈-alkylamino, di(C₁-C₈-alkyl)amino or a 5 or6-membered heterocyclic ring having one or more ring hetero atomsselected from the group consisting of oxygen, nitrogen and sulphur, thatring being optionally substituted by C₁-C₈-alkyl; R¹⁰ is hydrogen orC₁-C₈-alkyl; or R⁹ and R¹⁰ together with the nitrogen atom to which theyare attached form a 5 or 6-membered heterocyclic ring that contains oneor more further hetero atoms selected from the group consisting ofoxygen, nitrogen and sulphur, that ring being optionally substituted byC₁-C₈-alkyl; and R¹² and R¹³ together with the nitrogen atom to whichthey are attached form a 5 or 6-membered heterocyclic ring that containsone or more further hetero atoms selected from the group consisting ofoxygen, nitrogen and sulphur, that ring being optionally substituted byC₁-C₈-alkyl.
 7. A compound according to claim 6 wherein R¹ isC₁-C₈-alkylcarbonyl optionally substituted by carboxy orC₁-C₈-alkoxycarbonyl; R² is C₁-C₃-alkyl; R⁵ is hydrogen or halogen; R³is hydrogen, hydroxy, amino, SO₂R⁸, SO₂NH₂, SO₂NR⁹R¹⁰, NHSO₂R⁸, cyano,carboxy, OR⁸ or C₁-C₄-haloalkyl; R⁴ is NR¹²R¹³; R⁸ is C₁-C₈-alkyl; R⁹ isC₁-C₈-alkyl or C₃-C₈-cycloalkyl, optionally substituted by hydroxy,C₁-C₈-alkoxy, nitrile, di(C₁-C₈-alkyl)amino or a 5 or 6-memberedheterocyclic ring having one or more ring hetero atoms selected from thegroup consisting of oxygen and nitrogen, that ring being optionallysubstituted by C₁-C₈-alkyl; R¹⁰ is hydrogen or C₁-C₈-alkyl; or R⁹ andR¹⁰ together with the nitrogen atom to which they are attached form a 5or 6-membered heterocyclic ring that contains one or more further heteroatoms selected from the group consisting of oxygen and nitrogen, thatring being optionally substituted by C₁-C₅-alkyl; and R¹² and R¹³together with the nitrogen atom to which they are attached form a 5 or6-membered heterocyclic ring that contains one or more further heteroatoms selected from the group consisting of oxygen and nitrogen, thatring being optionally substituted by C₁-C₈-alkyl.
 8. A compound of claim1, that is also a compound of formula XIX

in free or salt form, wherein R^(a), R^(b), R^(c) and R¹ are as shown inthe following table: R^(a) R^(b) R^(c) R¹

H

H

H

H

H

H

H

H


9. A compound of claim 1, that is also a compound of formula XIX

in free or salt form, wherein R^(a), R^(b), R^(c) and R¹ are as shown inthe following table: R^(a) R^(b) R^(c) R¹

H

H


10. A pharmaceutical composition comprising a compound according toclaim 1 in combination with at least one drug substance which is ananti-inflammatory, a bronchodilator or an antihistamine drug substance.11. A pharmaceutical composition comprising as active ingredient acompound according to claim 1, optionally together with apharmaceutically acceptable diluent or carrier.
 12. A pharmaceuticalcomposition comprising as active ingredient a compound according toclaim 8, optionally together with a pharmaceutically acceptable diluentor carrier.
 13. A pharmaceutical composition comprising as activeingredient a compound according to claim 9, optionally together with apharmaceutically acceptable diluent or carrier.
 14. A compound of claim1, which compound has the formula:

in free or salt form.